Forty-five benign and 11 malignant gastrointestinal stromal tumors (GIST) were immunohistochemically studied for the presence of desmin, muscle actins (MA) and S-100 protein. To facilitate the analysis, the tumors were divided into four groups by light microscopy: (1) typical leiomyomas comparable to peripheral leiomyomas (n = 9); (2) cellular spindle cell tumors (n = 29); (3) round cell tumors ("leiomyoblastomas" n = 7); and (4) sarcomas (n = 11). The typical leiomyomas were desmin- and MA-positive throughout, and showed well-differentiated smooth muscle cells by electron microscopy, similar to the normal gastric smooth muscle cells. All esophageal leiomyomas belonged to this group. Nineteen of 29 of the Group 2 tumors showed desmin positivity and 20 of 29 showed MA positivity, but usually only in less than 10% of the tumor cells, and in many instances it was very difficult to determine whether the positive cells were real tumor cells or entrapped muscle cells. Only 5 of 29 of Group 2 tumors showed widespread desmin positivity and 11 of 29 showed similar MA positivity. Of round cell tumors, only 1 of 7 showed desmin-positive cells and 3 of 7 MA-positive cells. None of the sarcomas showed desmin, while MA positivity was found in 6 of 11 cases, often in a large number of tumor cells. Seven tumors showed a significant number of S-100 positive tumor cells, but four of these also showed a high number of desmin- and MA-positive cells, suggesting that these tumors represented complex proliferations of muscle and Schwann cell elements. Two purely S-100 positive benign probably Schwann cell-like tumors were found, both in the small bowel. Small number of S-100 positive cells were commonly found in GIST, and these probably represented entrapped Schwann cells, because many tumors showed simultaneous proliferation of non-neoplastic nerves.