Meningiomas are the most common primary cranial tumor arising in the central nervous system and its coverings, constituting 35.5% of primary brain tumors. Schwannomas account for 8.3% of primary neoplasms of the central nervous system. Occasionally these tumors can show overlapping morphology, most conspicuously in the fibrous variant of meningioma. In such cases, immunohistochemistry can help to establish a definitive diagnosis. Currently S100 is the most commonly used immunohistochemical stain to show neural crest differentiation in tumors. This may lead to potential misclassification of meningeal tumors, as up to 70% of fibrous meningiomas can show S100 expression. Our study sought to determine if Sox10 would prove a more specific alternative to S100 in cases of meningioma when the differential diagnosis includes schwannoma. We compared the mRNA expression of S100B and Sox10 using the publicly available GSE16581 meningioma dataset. We then studied Sox10 and S100 protein expression using immunohistochemistry in 147 cases of meningioma using tissue microarrays (TMA) and 19 cases of fibrous meningioma using full cross-sections (FCS). Sox10 and S100B mRNA expression in GSE16581 showed no significant correlation in meningothelial tumors (r=-0.002, P=0.989). By immunohistochemistry, S100 was positive in 14/19 (73.7%) of FCSs and 71/147 (48.3%) of TMA tumors, whereas Sox10 (protein name) was positive in only 1/19 (5.3%) of FCSs and 3/147 (2.0%) of TMA tumors. In summary, Sox10 is superior to S100 in the differential diagnosis of schwannoma and meningioma.