Curative resection is typically recommended for treating gastrointestinal stromal tumors (GISTs). Exceptions are made for locally advanced GISTs (LAGISTs) where radical resection may be impossible. First-line imatinib therapy can be employed to treat GISTs harboring mutations in the tyrosine-protein kinase KIT () and platelet-derived growth factor receptor α () genes to reduce the tumor size to resectable levels and minimize surgical risks. The present study investigated the treatment outcomes of patients with LAGISTs with different and gene mutations who received first-line imatinib therapy. A total of 37 patients with LAGISTs who underwent first-line imatinib treatment were included, and the median follow-up period was 41 months. Treatment regimens included imatinib, with subsequent therapies, such as sunitinib and regorafenib, administered upon imatinib failure. The genetic profiles of and were analyzed. Of the 37 patients, 24 (64.9%) successfully underwent curative resection. The median progression-free survival (PFS) was 36 months and the median overall survival (OS) was 41 months. Patients presented with tumors with various genetic mutations, which differentially affected their PFS and OS and adverse events were typically manageable. However, the gene mutation status was not significantly associated with treatment response or surgical resectability (both P>0.05). The present study elucidated the effects of first-line therapy on LAGISTs with genetic mutations, underscoring the effectiveness of imatinib treatment and the value of continual patient monitoring. Additional studies with long-term follow-up are required to evaluate treatment outcomes.