An immunohistochemical study to determine the pattern of immunoreactivity for bcl-2 oncoprotein was performed in 380 spindle cell tumors of soft tissue, skin, serosal surfaces, and gastrointestinal tract. The cases studied included examples of benign, reactive spindle cell proliferations to benign and malignant spindle cell neoplasms, including nodular fasciitis (10), fibromatosis (5), dermatofibroma (10), dermatofibrosarcoma protuberans (18), Kaposi's sarcoma (15), spindle cell lipomatous tumors (24), benign and malignant smooth muscle tumors (35), neural/peripheral nerve sheath neoplasms (53), synovial sarcomas (70) solitary fibrous tumors of serosal surfaces and other sites (56), gastrointestinal stromal tumors (GIST) (47), and malignant undifferentiated fibroblastic spindle cell proliferations of soft tissue (37 cases). The results of bcl-2 staining was additionally correlated with CD34 immunoreactivity. Bcl-2 was uniformly negative in all cases of nodular fasciitis, fibromatosis, and dermatofibroma, as well as in benign and malignant smooth muscle proliferations. Strong positivity for bcl-2 was observed in all cases of spindle cell lipoma, dendritic fibromyxolipoma, Kaposi's sarcoma, solitary fibrous tumors, gastrointestinal stromal tumors, and in the spindle cell component of synovial sarcoma. With the exception of the last, there appeared to be a close correlation between the expression of bcl-2 and CD34 in these tumors. Strong bcl-2 positivity also was found, at least focally, in approximately one third of benign and malignant peripheral nerve sheath tumors, particularly in the better-differentiated (Antoni type A) areas. Sarcomas of fibroblastic type, including low-grade myxofibrosarcoma, malignant fibrous histiocytoma, and fibrosarcoma, showed variable expression of bcl-2 in the tumor cells. Our results appear to indicate that bcl-2 may have a wide distribution among benign and malignant spindle cell neoplasms. Strong expression of this marker in some of these conditions, particularly solitary fibrous tumor, gastrointestinal stromal tumors, and synovial sarcoma, may be of aid for differential diagnosis.