We studied 25 cases of schwannoma and 42 cases of neurofibroma immunohistochemically with antibodies to calretinin and S-100 protein to explore the potential usefulness of calretinin in differentiating schwannomas from neurofibromas. Of 25 schwannomas, 24 (96%) showed moderate to strong staining for calretinin, with the extent of staining ranging from focal to diffuse. In contrast, only 3 (7%) of 42 neurofibromas displayed focal weak to moderate staining with calretinin. All 42 cases of neurofibromas and all 25 cases of schwannomas showed diffuse moderate to strong staining with S-100 protein. Calretinin also labeled mast cells, whose presence was confirmed further by staining for c-kit, which commonly was present in both tumor types in a scattered individual cell pattern easily differentiated from the clustered pattern of neoplastic spindle cells. Taken together, these results indicate that calretinin is detected in almost all schwannomas and in only a small percentage of neurofibromas, suggesting it is a useful marker for differentiating schwannomas from neurofibromas. Although mast cells present in these 2 neoplasms also react with calretinin, the pattern of staining can be distinguished easily from that of neoplastic cells.