Objective: To explore the clinical effect of imatinib targeted therapy on high risk gastrointestinal stromal tumor (GISTS). Methods: The clinical data of 56 patients with high risk GIST undergoing imatinib targeted therapy from January 2010 to June 2015 were reviewed, and the therapeutic efficacy was analyzed. Results: Nineteen patients, who had no chance of surgical resection, received imatinib (400 mg/d) therapy for 6 to 8 months, and of them, none achieved complete response (CR), 14 cases obtained partial response (PR), 4 cases had stable disease (SD), and one case presented progressive disease (PD); 7 PR cases (36.8%) obtained a chance for tumor resection. Thirty-five patients received imtinib (400 mg/d) treatment for one year after surgical resection, and of them, recurrence occurred in 3 cases (8.6%) during follow-up and the one-year recurrence rate was 8.6%; 2 cases did not continue to take the medication and their results could not be determined. Conclusion: Imatinib has significant efficacy in GIST patients, and in those with high risk GIST, its preoperative neoadjuvant chemotherapy may offer a chance of surgical resection for the unresectable tumors, and its postoperative adjuvant chemotherapy may improve the tumor-free survival with tolerable adverse effects.