We report two cases of postoperative recurrence of gastrointestinal stromal tumor (GIST) treated by the tyrosine kinase inhibitor imatinib mesylate (IM), and discuss some important items. Case 1: This 63-year-old Japanese man received a partial gastrectomy for leiomyosarcoma in 1993. Partial hepatectomy and proximal gastrectomy were performed for liver metastasis and local recurrence in 2001. However, 5 months after surgery, a CT scan showed multiple tumors in the liver, lung and thyroid. The patient was treated with 300 mg of IM once daily with transient grade 2 neutropenia and intestinal bleeding. Though the response to treatment was SD-PR initially, a CT scan 15 months after initial treatment demonstrated the regrowth of the tumor in his liver. Case 2: A 63-year-old Japanese woman was treated with 200 mg of IM once daily for multiple liver metastases after gastrectomy for GIST with grade 3 neutropenia and edema of legs. The response to treatment was SD, and continued for 12 months. IM is the treatment of choice for unresectable recurrence of GIST. However, some problems remained. Both basic and clinical research is necessary to increase the therapeutic efficacy of IM.