HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12pts received 600mg twice a week (BIW) and 11 patients received 400mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021. The median age was 59 years (33–88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25–138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5µmol and the mean AUC was 2.9µmolh. Cmax >1.5µmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.