The benefits of surgery for focally progressive gastrointestinal stromal tumor (GIST) during imatinib therapy are still in discussion. The aim of this study was to compare the outcomes of surgical resection of progressive lesions following tyrosine kinase inhibitor (TKI) therapy (S group) or TKI therapy alone (NS group) in GIST patients. We retrospectively investigated 57 patients with focally progressive GIST during imatinib therapy who were treated in Zhongshan hospital, Fudan University. Progression-free survival (PFS) and overall survival (OS) in the S group were significantly longer than those in the NS group. Among S group, the patients with R0 resection showed longer PFS than R2 resection; however, no difference was found between these two groups. Moreover, PFS and OS were not different in the NS-S group compared with S group. On multivariate analysis, surgery is an independent prognostic factor for longer PFS and OS. Our study supports the decision of treating GIST patients who were focally resistant to imatinib with surgery resection based on its benefit.