For further characterization of S-100 protein-positive granular cell tumor (GCT), the expression of osteopontin (OPN) in the tumor cells was compared with other types of Schwannian cell tumors. Twenty GCT, three amputation neuromas, 12 neurilemmomas (NM) and three malignant peripheral nerve sheath tumors (MPNST) were used. In addition, two granular cell epulides were employed because of histological similarity to that of GCT. Immunohistochemistry by anti-OPN-monoclonal antibody revealed OPN-immunoreactivity in tumor cells of all GCT and stromal macrophages in neurilemmomas and one MPNST, but neither in amputation neuromas nor in granular cell epulides. All nine GCT studied by in situ hybridization (ISH) and all three GCT analyzed by reverse transcription-polymerase chain reaction (RT-PCR) were positive for OPN mRNA. In contrast, seven NM and three amputation neuromas were negative for OPN mRNA by either ISH or RT-PCR, while macrophages infiltrated in these tumors had OPN mRNA consistently. Double immunostaining for OPN and CD68, a lysosome-associated glycoprotein, showed their colocalization in tumor cells of GCT, suggesting a possible degradation of OPN by lysosomes. In conclusion, GCT among Schwannian cell tumors consistently express OPN, but its biological significance requires further investigation.