Background: This prospective, multicenter, phase II study evaluated the efficacy and safety of sorafenib in patients (pts) with advanced gastrointestinal stromal tumors (GISTs) who failed previous standard tyrosine kinase inhibitors (TKI). Methods: Thirty-one patients with pathologically proven metastatic or unresectable GISTs who failed both imatinib and sunitinib were accrued between Dec 2009 and Jun 2010. Sorafenib was administered orally at 400 mg twice daily. Results: Among 31 pts, 23 (74%) were male. The median age was 59 years (range, 31-78). All had metastatic disease in the liver (n=27), peritoneum (n=19), lung (n=4), or bone (n=1). Ten pts (32%) received nilotinib as a third line treatment after the failure of imatinib and sunitinib. The primary sites were stomach (n=10) and small bowel (n=21). With sorafenib, 3 pts (10%) achieved a partial response and 17 pts (55%) had stable disease. With a median follow-up of 7.5 months (range, 5.0-12.6), the median progression-free survival (PFS) was 4.9 months (95% CI, 1.6-8.2) and the disease control rate was 37.6% at 6 months. Pts with prior use of 3^rd line nilotinib and primary genotypes other than mutations at KIT exon 11 showed significantly worse PFS (p=0.0085 and p=0.0341, respectively). Median OS has not been reached yet. Grade 3 or 4 adverse events of sorafenib with frequency > 5% of pts included hand-foot skin reaction (16%), fatigue (7%), hypertension (7%), and abdominal pain (7%). Those toxicities were manageable with dose modification (n=10), and there was no treatment-related death. The relative dose intensity during the first 6 cycles was generally over 80%. Conclusions: Sorafenib was effective as a salvage treatment with manageable toxicities in GIST pts who failed prior standard TKIs. With sorafenib, about one third of pts can maintain disease stabilization for more than 6 months. Further randomized controlled trials are needed to confirm the efficacy of our results.