The term "gastrointestinal stromal tumor" (GIST) has been applied to mesenchymal tumors that represent neither typical leiomyomas nor schwannomas. In this study we analyzed immunohistochemically 67 histologically benign [< 2 mitoses/10 high-power field (HPF)], six borderline (3-5 mitoses/10 HPF), and 23 malignant GIST (> 5 mitoses/10 HPF) and compared them with 10 typical leiomyomas and 5 schwannomas of the gastrointestinal tract. The benign GISTs with spindle cell pattern (67 cases) were typically negative for muscle cell markers (only 3% positive for desmin and 25% for alpha-smooth muscle actin) and S100 protein, but 70% of the cases were positive for CD34, the myeloid progenitor cell antigen also present in endothelial cells and some fibroblasts. However, none of the cases was positive for CD31 (PECAM-1), a more endothelial cell-specific antigen. The absence of CD31 in GIST separates it from Kaposi's sarcoma, a tumor known to be positive for both CD34 and CD31. Fourteen cases of benign GIST of epithelioid cell type showed an immunophenotypic profile similar to the spindle cell tumors. The small intestinal tumors were more commonly actin positive and less commonly CD34 positive than were the gastric tumors. The malignant spindle and epithelioid GIST showed features essentially similar to those in corresponding benign tumors. In contrast, all typical leiomyomas were positive for muscle cell markers and were negative for CD34 and S100 protein. Gastrointestinal schwannomas were S100-protein positive, and negative for muscle markers and CD34. Our results show that gastrointestinal mesenchymal tumors can be immunophenotypically divided in categories that correlate with light microscopically defined diagnostic entities, namely typical leiomyomas, schwannomas, and GIST, most cases of the latter representing tumors of primitive mesenchymal cells that are CD34 positive.