AIM: To investigate the role of angiopoietin (Ang) -1,-2 and -4 and its receptors, Tie-1 and -2, in the growth and differentiation of gastrointestinal stromal tumors (GISTs).METHODS: Thirty GISTs, seventeen leiomyomas and six schwannomas were examined by immunohistochemistry in this study.RESULTS: Ang-1, -2 and -4 proteins were expressed in the cytoplasm of tumor cells, and Tie-1 and -2 were expressed both in the cytoplasm and on the membrane of all tumors. Immunohistochemical staining revealed that 66.7% of GISTs (20 of 30), 76.5% of leiomyomas (13 of 17) and 83.3% of schwannomas (5 of 6) were positive for Ang-1. 83.3% of GISTs (25 of 30), 82.4% of leiomyomas (14 of 17) and 100% of schwannomas (6 of 6) were positive for Ang-2. 36.7% of GISTs (11 of 30), 58.8% of leiomyomas (10 of 17) and 83.3% of schwannomas (5 of 6) were positive for Ang-4. 60.0% of GISTs (18 of 30), 82.4% of leiomyomas and 100% of schwannomas (6 of 6) were positive for Tie-1. 10.0% of GISTs (3 of 30), 94.1% of leiomyomas (16 of 17) and 33.3% of schwannomas (2 of 6) were positive for Tie-2.Tie-2 expression was statistically different between GISTs and leiomyomas (P ＜ 0.001). However, there was no correlation between expression of angiopoietin pathway components and clinical risk categories.CONCLUSION: Our results suggest that the angiopoietin pathway plays an important role in the differentiation of GISTs, leiomyomas and schwannomas.