Background: Imatinib mesylate (IM), which inhibits the KIT and PDGFR tyrosine kinases, has known activity against GIST. We previously reported early results of the first reported multi-institutional prospective trial (RTOG 0132) using neoadjuvant imatinib mesylate (IM) either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic GIST (Eisenberg et al., JSO 2009). Methods: Patients with primary GIST (≥5cm, Group A) or operable metastatic/recurrent GIST (≥2 cm, Group B) received neoadjuvant IM (600 mg/day) for approximately two months and maintenance IM after surgery for 2 years. We have now updated the clinical outcomes including progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) at a median follow-up of 5.1 years and correlate these endpoints with duration of IM therapy. Results: Sixty-three patients were originally entered (53 analyzable), 31 patients in Group A and 22 in Group B. Estimated 5-year PFS and DSS were 57% A, 30% B; and 77% A, 77% B, respectively. Estimated 5-year OS was 77% for A, and 68% for B. Median time to progression has not been yet reached for Group A and is 4.4 years for Group B. In Cohort A, 7/11 patients progressed > 2 years from registration; 6/7 progressing patients had stopped IM prior to progression. In Cohort B, 10/13 patients progressed> 2 years from registration; 6/10 progressing patients had stopped IM prior to progression. The rate of treatment-related grade 4/5 toxicities was 23% (12/53). There was no increase in long term surgical complications using neoadjuvant and extended IM therapy. Conclusions: This long-term analysis of RTOG 0132 suggests a high percentage of patients progressed after discontinuation of 2-year maintenance IM therapy following surgical resection. Consideration should be given to studying longer treatment durations in high-risk GIST patients.