The histogenesis of stromal tumors of the gastrointestinal tract (GIST) is still controversial. Recent immunohistologic and ultrastructural studies have been inconsistent and suggest various cells of origin. In view of these uncertainties, we studied the immuno-profiles of 82 cases of GISTs and 11 cases of stromal tumors that we classified as leiomyomas based on histology. The 82 cases of GIST were subclassified as spindle or epithelioid type stromal tumors based on the predominant pattern and further divided into benign (< 5 cm in size and < 5 mitosis/50 HPF), malignant (> 5 mitosis/50 HPF), and borderline lesions (> 5 cm and < 5 mitosis/50 HPF). A panel of antibodies was used to characterize differentiation toward myogenic cells [pan-muscle actin (HHF-35), alpha-smooth muscle actin (SMA) and desmin], Schwann cells (S-100 protein), enteric glial [(glial fibrillary acidic protein (GFAP)], and nerve cells (neurofilaments). All leiomyomas were strongly positive for the three muscle markers. Of the 82 GISTs, only four cases (5%) were positive for desmin. However, 63% (52 cases) were positive with anti-pan-muscle actins and 39% (32 cases) were positive with anti-SMA. Compared with gastric tumors, the positivity rates were much higher for small bowel tumors. Seventy-nine cases (96%) were positive for vimentin, only five cases and two cases were focally and weakly reactive for S-100 protein and GFAP respectively, and none stained for neurofilaments.(ABSTRACT TRUNCATED AT 250 WORDS)