AIM: To explore the influence of imatinib as adjuvant therapy on relapse-free survival in patients with gastrointestinal stromal tumors (GISTs) at moderate to high risk of recurrence. METHODS: Sixty-five patients with GISTs at moderate to high risk of recurrence who were treated at our hospital from March 2006 to January 2009 were retrospectively analyzed. The short term curative effect and relapse were evaluated. The patients were divided into different groups according to imatinib treatment time, and the differences in relapse, relapse-free survival and adverse reactions were compared between different groups. RESULTS: Complete remission was achieved in 5 (7.69%) cases, partial remission in 44 (67.69%) cases, stable disease in 13 (20.0%) cases, and progressive disease in 3 (4.62%) cases. The overall response rate was 75.38% (49/65), and disease control rate was 95.38% (62/65). Twelve (18.46%) patients developed tumor recurrence. With the increase in imatinib treatment time, the relapsefree survival rates of patients at 1, 2, 3, 4 and 5 years showed a rising trend. The relapse-free survival rates at 1, 2, 3 and 4 years were all 100%, and it was 95.24% at 5 years. The 5-year relapsefree survival rate (92.11%) in the treatment ≥ 3 years group was significantly higher than that in the < 3 years group (59.26%)(P = 0.026); the 5-year relapse-free survival rate (95.65%) in the ≥ 3 years group was higher than that in the 3 years group (92.59%), but there was no significant difference (P = 0.168). Imatinib toxicities mainly included blood toxicity, digestive tract toxicity, skin and mucosal edema, and debilitation, and most of these toxicities were mild (grades 0-2) and improved after symptomatic treatment. The incidence of debilitation in the ≥ 3 years group was significantly higher than that in the < 3 years group (P < 0.05). CONCLUSION: For patients with GISTs at moderate to high risk of recurrence, prolonged postoperative imatinib adjuvant treatment to more than 3 years can improve relapse-free survival time to some extent. Except for the significantly increased incidence of debilitation, the incidence of other adverse reactions showed no significant rise.