By using the D2-40 antibody, we have observed podoplanin expression in Schwann cells and perineurial cells. Podoplanin expression has not been well characterized in peripheral nerve sheath tumors. Because neoplasms of neural crest lineage, including peripheral nerve sheath and melanocytic neoplasms, may share histologic and immunohistochemical characteristics, we evaluated podoplanin and S-100 expression in these lesions to determine the usefulness of podoplanin as a diagnostic marker. Diffuse podoplanin and S-100 expression was observed in 16 (76%) of 21 classical schwannomas, 6 (100%) of 6 cellular schwannomas, and 3 (75%) of 4 epithelioid malignant peripheral nerve sheath tumors (EMPNSTs). Podoplanin was expressed in 3 (7%) of 43 neurofibromas, 16 (21%) of 75 spindle cell MPNSTs (SMPNSTs), and 1 (10%) of 10 spindle cell melanomas but was absent in conventional melanoma. Only rare neurofibromas and SMPNSTs showed strong coexpression of podoplanin and S-100. These results suggest diffuse podoplanin expression or coexpression of podoplanin and S-100 is limited to schwannoma and EMPNST and may be useful in the evaluation of these neoplasms.