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AIM: To investigate the role that the hedgehog (Hh)signaling pathway, which includes sonic hedgehog (Shh),Patched (Ptc), Smoothened (Smo) and Gli-1, plays in human gastrointestinal stromal tumors (GISTs).METHODS: Surgically resected specimens from patients with GISTs, leiomyomas and schwannomas were examined by immunohistochemical staining for aberrant expression of hedgehog signaling components, Shh, Ptc,Smo and Gli-1, respectively.RESULTS: In GISTs, 58.1% (18 of 31), 77.4% (24 of 31), 80.6% (25 of 31) and 58.1% (18 of 31) of the specimens stained positive for Shh, Ptc, Smo and Gli-1,respectively. In leiomyomas, 92.3% (12 of 13), 92.3% (12 of 13), 69.2% (9 of 13) and 92.3% (12 of 13) stained positive for Shh, Ptc, Smo and Gli-1, respectively. In schwannomas, 83.3% (5 of 6), 83.3% (5 of 6), 83.3%(5 of 6) and 100% (6 of 6) stained positive for Shh,Ptc, Smo and Gli-1, respectively. Immunohistochemistry revealed that the expressions of Shh and Gli-1 were significantly higher in leiomyomas than in GISTs (P ＜ 0.05,respectively). Shh expression strongly correlated with the grade of tumor risk category and with tumor size (P ＜0.05, respectively). However, the expressions of Ptc and Smo did not correlate with histopathological differentiation.CONCLUSION: These results suggest that the Hh signaling pathway may play an important role in myogenic differentiation and the malignant potential of human intestinal stromal tumors.