Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor targeting all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib has shown tolerability and superior progression-free survival and overall response rate versus sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma. Final overall survival (OS) data (August 27, 2012) from TIVO-1 and its open-label, multicenter extension study are reported. Methods: A total of 517 patients were randomized 1:1 to tivozanib 1.5 mg/d (3 weeks on, 1 week off) or sorafenib 400 mg/d (twice a day, continuously) (J Clin Oncol2012;30[suppl]:Abstract 4501). In the extension study, patients who progressed (PD) on sorafenib based on investigator assessment were eligible to receive tivozanib, and patients with PD on tivozanib received subsequent treatment according to regional standards of care. Final OS analysis was planned to be conducted after all patients had died or were lost to follow-up, or when all patients in follow-up had been on study for at least 2 years, whichever occurred first. OS was compared using the stratified log-rank test. OS distribution was estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazard regression model. Results: At the time of final OS analysis (2 years after last patient was enrolled), 219 deaths had occurred (tivozanib, n=118 [45.4%]; sorafenib, n=101 [39.3%]) (stratified HR=1.245; 95% confidence interval [CI] 0.954–1.624; p=0.105), trending in favor of the sorafenib arm. Median OS (95% CI) was 28.8 months (22.5–NA) for tivozanib and 29.3 months (29.3–NA) for sorafenib. Of the 257 patients on sorafenib, 155 (60.3%) had started next-line tivozanib at the time of the analysis. Conclusions: There was no significant difference in OS between the two treatment arms. The high rate of utilization of second-line tivozanib in patients following PD on sorafenib may have affected the OS outcome. Clinical trial information: NCT01030783.