Vasculogenic mimicry (VM) is the formation of fluid-conducting channels by highly invasive and genetically dysregulated tumor cells. In this study, we collected specimens of 84 human gastrointestinal stromal tumors (GISTs) along with clinicopathologic data and another 42 GISTs with fresh tissue that was used for gelatin zymography. VM was found in 21 of the 84 GISTs using CD31/periodic acid-Schiff double staining and CD117 and CD31 immunohistochemical staining. There was a significant difference in the VM-positive rate between the lesions with a mitotic rate > or =5/50 high-power fields and those with a lower mitotic rate (P = .000) and between the cases with and without liver metastasis (P = .008). There was a significant difference in the VM-positive rate between the high-risk group (5.9%) and the very low/low-risk group (12.5%) (P = .010) or the intermediate-risk group (39.5%) (P = .020). Kaplan-Meier survival analysis showed VM indicated a poor prognosis (P = .0000). Cox proportional hazards model indicated that the presence of VM, tumor size 10 cm or greater, and hemorrhage were independent predictors of a poor prognosis (P = .000, .005, .032, respectively). The staining indexes of matrix metalloproteinase (MMP)-2 and MMP-9 were higher in the VM-positive than in the VM-negative group (P = .024 and .037, respectively). Gelatin zymography showed that the activity of MMP-2 and MMP-9 was significantly higher in the VM-positive lesions (P = .013 and .033, respectively). We conclude that VM in GISTs is an unfavorable prognostic sign and that patients with VM-positive tumors are prone to suffer liver metastasis. Both MMP-2 and MMP-9 play an important role in VM formation in GISTs.