diff --git a/pyproject.toml b/pyproject.toml
index e5edc4d..34619c2 100644
--- a/pyproject.toml
+++ b/pyproject.toml
@@ -20,7 +20,7 @@ classifiers = [
 license = "BSD-3-Clause"
 license-files = ["LICEN[CS]E*"]
 dependencies = [
-    "cap-anndata>=0.5.0",
+    "cap-anndata>=0.5.2",
     "numpy>=2.0.2",
     "pandas>=2.2.3",
     "scipy>=1.13.1",
diff --git a/src/cap_upload_validator/errors.py b/src/cap_upload_validator/errors.py
index c77e7a1..b766819 100644
--- a/src/cap_upload_validator/errors.py
+++ b/src/cap_upload_validator/errors.py
@@ -113,3 +113,18 @@ class AnnDataNonStandardVarError(CapException):
             If there are other species you wish to upload to CAP, please contact
             support@celltype.info and we will work to accommodate your request.
         """ 
+
+class CSCMatrixInX(CapException):
+    name = "CSCMatrixInX"
+
+    def __init__(self, locations: list[str]):
+        """
+        locations: list of matrix locations, e.g. ['X'], ['raw.X'], or ['X', 'raw.X']
+        """
+        super().__init__()
+        self.locations = locations
+        loc_str = " and ".join(locations)
+        self.message = (
+            f"The CSC matrix is found in {loc_str}. "
+            "Gene expression matrix must be stored in CSR or dense format!"
+        )
diff --git a/src/cap_upload_validator/upload_validator.py b/src/cap_upload_validator/upload_validator.py
index a3eb219..b425158 100644
--- a/src/cap_upload_validator/upload_validator.py
+++ b/src/cap_upload_validator/upload_validator.py
@@ -3,7 +3,7 @@
 from scipy.sparse import issparse
 from cap_anndata import CapAnnData, read_h5ad
 import logging
-from h5py import Dataset
+from h5py import Dataset, Group
 
 from .gene_mapping import (
     GeneMap,
@@ -22,6 +22,7 @@
     AnnDataNonStandardVarError,
     BadAnnDataFile,
     AnnDataNoneInGeneralMetadata,
+    CSCMatrixInX,
 )
 from typing import Optional
 
@@ -68,6 +69,7 @@ def validate(self, report_success: bool = True) -> None:
             if cap_adata.raw is not None:
                 cap_adata.raw.read_var(columns=[])
 
+            self._validate_x_and_raw_x_formats(cap_adata)
             self._check_X(cap_adata)
             self._check_obsm(cap_adata)
             self._check_obs(cap_adata)
@@ -287,3 +289,48 @@ def _remove_gene_version(ensemble_ids: pd.Index) -> pd.Index:
         clean_index = ensemble_ids.to_series().apply(lambda x: x.split(".")[0])
         clean_index = pd.Index(clean_index)
         return clean_index
+
+    def _is_csc(self, group_or_dataset) -> bool:
+        """
+        Returns True if HDF5 object represents a CSC sparse matrix.
+        """
+        if not isinstance(group_or_dataset, Group):
+            return False
+
+        encoding = group_or_dataset.attrs.get("encoding-type", None)
+        return encoding == "csc_matrix"
+
+    def _is_csr(self, group_or_dataset) -> bool:
+        if not isinstance(group_or_dataset, Group):
+            return False
+        return group_or_dataset.attrs.get("encoding-type", None) == "csr_matrix"
+
+    def _is_dense(self, group_or_dataset) -> bool:
+        return isinstance(group_or_dataset, Dataset)
+
+    def _validate_x_and_raw_x_formats(self, cap_adata: CapAnnData) -> None:
+        """
+        Validate that X and raw.X (if exists) are dense or CSR.
+        Raise CSCMatrixInX otherwise.
+        """
+        locations = []
+    
+        f = cap_adata.file
+    
+        # X
+        x = f["X"]
+        if self._is_csc(x):
+            locations.append("X")
+        elif not (self._is_dense(x) or self._is_csr(x)):
+            locations.append("X")
+
+        # raw.X
+        if "raw" in f and "X" in f["raw"]:
+            raw_x = f["raw/X"]
+            if self._is_csc(raw_x):
+                locations.append("raw.X")
+            elif not (self._is_dense(raw_x) or self._is_csr(raw_x)):
+                locations.append("raw.X")
+
+        if locations:
+            raise CSCMatrixInX(locations=locations)
diff --git a/test/test_upload_validator.py b/test/test_upload_validator.py
index 2725427..3d9c104 100644
--- a/test/test_upload_validator.py
+++ b/test/test_upload_validator.py
@@ -1,7 +1,12 @@
 import pytest
 import numpy as np
 import pandas as pd
+
 import anndata as ad
+from packaging import version
+if version.parse(ad.__version__) >= version.parse("0.11.0"):
+    ad.settings.allow_write_nullable_strings = True
+
 import scipy.sparse as sp
 from pathlib import Path
 import tempfile
@@ -27,6 +32,7 @@
     AnnDataNonStandardVarError,
     CapMultiException,
     AnnDataNoneInGeneralMetadata,
+    CSCMatrixInX,
 )
 
 TMP_DIR = Path(tempfile.mkdtemp())
@@ -262,3 +268,75 @@ def test_ontology_id_instead_general_metadata(names_provided, with_none):
         with context:
             adata.read_obs(GENERAL_METADATA)
             v._check_obs(adata)
+
+
+def write_adata_with_matrix(path, X, raw_X=None):
+    adata = ad.AnnData(X=X)
+
+    if raw_X is not None:
+        adata.raw = ad.AnnData(X=raw_X)
+
+    adata.write_h5ad(path)
+
+
+def test_csc_in_x_raises(tmp_path):
+    p = tmp_path / "test.h5ad"
+
+    X = sp.csc_matrix(np.eye(5)) # CSC
+    write_adata_with_matrix(p, X=X)
+
+    v = UploadValidator(p)
+
+    with pytest.raises(CSCMatrixInX) as e:
+        with read_h5ad(p, edit=False) as cap_adata:
+            v._validate_x_and_raw_x_formats(cap_adata)
+
+    assert "X" in e.value.message
+
+
+def test_csc_in_raw_x_raises(tmp_path):
+    p = tmp_path / "test.h5ad"
+
+    X = sp.csr_matrix(np.eye(5)) # valid CSR
+    raw_X = sp.csc_matrix(np.eye(5)) # invalid CSC
+
+    write_adata_with_matrix(p, X=X, raw_X=raw_X)
+
+    v = UploadValidator(p)
+
+    with pytest.raises(CSCMatrixInX) as e:
+        with read_h5ad(p, edit=False) as cap_adata:
+            v._validate_x_and_raw_x_formats(cap_adata)
+
+    assert "raw.X" in e.value.message
+
+
+def test_csc_in_both_raises(tmp_path):
+    p = tmp_path / "test.h5ad"
+
+    X = sp.csc_matrix(np.eye(5))
+    raw_X = sp.csc_matrix(np.eye(5))
+
+    write_adata_with_matrix(p, X=X, raw_X=raw_X)
+
+    v = UploadValidator(p)
+
+    with pytest.raises(CSCMatrixInX) as e:
+        with read_h5ad(p, edit=False) as cap_adata:
+            v._validate_x_and_raw_x_formats(cap_adata)
+
+    assert "X and raw.X" in e.value.message
+
+
+def test_dense_and_csr_pass(tmp_path):
+    p = tmp_path / "test.h5ad"
+
+    X = np.random.rand(5, 5) # valid dense
+    raw_X = sp.csr_matrix(np.eye(5)) # valid CSR
+
+    write_adata_with_matrix(p, X=X, raw_X=raw_X)
+
+    v = UploadValidator(p)
+
+    with read_h5ad(p, edit=False) as cap_adata:
+        v._validate_x_and_raw_x_formats(cap_adata) # should not raise
diff --git a/uv.lock b/uv.lock
index 6b3bef6..68b347a 100644
--- a/uv.lock
+++ b/uv.lock
@@ -1,5 +1,5 @@
 version = 1
-revision = 2
+revision = 3
 requires-python = ">=3.9"
 resolution-markers = [
     "python_full_version >= '3.12'",
@@ -65,7 +65,7 @@ wheels = [
 
 [[package]]
 name = "cap-anndata"
-version = "0.5.0"
+version = "0.5.2"
 source = { registry = "https://pypi.org/simple" }
 dependencies = [
     { name = "anndata", version = "0.10.9", source = { registry = "https://pypi.org/simple" }, marker = "python_full_version < '3.10'" },
@@ -74,14 +74,14 @@ dependencies = [
     { name = "numpy", version = "2.2.3", source = { registry = "https://pypi.org/simple" }, marker = "python_full_version >= '3.10'" },
     { name = "pandas" },
 ]
-sdist = { url = "https://files.pythonhosted.org/packages/12/b8/78a21f27e2eaa8c28a6855b2b6509ee3765139fede84042147f553e8a190/cap_anndata-0.5.0.tar.gz", hash = "sha256:8b288c1c948e068979eede4aa87b4375e91ba68ead36598a810e8e15077f580c", size = 16563, upload-time = "2025-05-30T13:06:23.545Z" }
+sdist = { url = "https://files.pythonhosted.org/packages/6f/41/f0ca38348b2f5be0c5ceaa524a672327dafa10fa0aaaf9cc4ae56fcd851e/cap_anndata-0.5.2.tar.gz", hash = "sha256:dff2d52fd9255eebd3c47982d0eb40036e8ff868585a5e688532d3c7cf2b9c79", size = 16584, upload-time = "2026-02-02T10:31:20.717Z" }
 wheels = [
-    { url = "https://files.pythonhosted.org/packages/f0/0d/823f21cafd2445301fe24a6524a4d71f0597047853d759add77d3b05914a/cap_anndata-0.5.0-py3-none-any.whl", hash = "sha256:2e634dcf13c4eecbacfacd76088dd149ce2eaa6a69cecda9032e1d29d2aa067f", size = 10551, upload-time = "2025-05-30T13:06:22.443Z" },
+    { url = "https://files.pythonhosted.org/packages/b1/3f/5f6f3b061fbd6b0af505fa5069f800560a1e656c6ac99aea24ea34e27627/cap_anndata-0.5.2-py3-none-any.whl", hash = "sha256:e5da884cc3a884c40c64dc105da44ec1969e60b6e5a2fd8b8444b229bb1180b7", size = 10584, upload-time = "2026-02-02T10:31:19.183Z" },
 ]
 
 [[package]]
 name = "cap-upload-validator"
-version = "1.3.1"
+version = "1.5.1"
 source = { editable = "." }
 dependencies = [
     { name = "cap-anndata" },
@@ -94,7 +94,7 @@ dependencies = [
 
 [package.metadata]
 requires-dist = [
-    { name = "cap-anndata", specifier = ">=0.5.0" },
+    { name = "cap-anndata", specifier = ">=0.5.2" },
     { name = "numpy", specifier = ">=2.0.2" },
     { name = "pandas", specifier = ">=2.2.3" },
     { name = "scipy", specifier = ">=1.13.1" },