Background: In a randomized phase II trial in treatment-naïve patients with metastatic renal cell carcinoma (mRCC), objective response rate (ORR) was significantly higher with axitinib versus placebo titration; the hazard ratio (HR) for progression-free survival (PFS) favored axitinib titration but was not statistically significant. Analysis of overall survival (OS; as of Nov 4, 2014) is reported. Methods: Previously untreated patients with mRCC (N = 213) received axitinib 5 mg twice daily (BID) for a 4-week lead-in period. Patients with 2 consecutive weeks of blood pressure ≤ 150/90 mmHg, no grade > 2 axitinib-related toxicities, no dose reductions, and ≤ 2 antihypertensive medications were randomized (double-blind) to axitinib 5 mg BID + dose titration to a maximum of 10 mg BID with axitinib or placebo (n = 56 each). Those ineligible for randomization continued the axitinib 5 mg BID dose (n = 91); 10 patients discontinued prior to randomization. Primary endpoint was ORR; PFS and OS were secondary endpoints. Results: As of the data cut-off date, 90 of 213 patients (42%) were censored for survival (45% in the axitinib titration arm vs 30% in the placebo titration arm; 46% in the nonrandomized arm); at least 75 censored patients were alive. Median OS (95% confidence interval [CI]) from first dose was 42.7 months (24.7–not estimable [NE]) in the axitinib titration arm versus 30.4 months (23.7–45.0) in the placebo titration arm (HR 0.785; 95% CI 0.485–1.272; P= 0.1616). Median OS (95% CI) in the nonrandomized arm was 41.6 months (33.0–NE). In all patients, median OS (95% CI) was 39.3 months (32.7–45.8). Safety data were consistent with previous reports. Following treatment periods > 3.5 years, 9 (16%), 1 (2%), and 10 (11%) patients remain on treatment in axitinib titration, placebo titration, and nonrandomized arms, respectively. Conclusions: Median OS exceeded 3 years in patients with mRCC treated with first-line axitinib. Median OS was numerically longer in patients receiving axitinib titration compared with placebo titration but did not reach statistical significance. A substantial percentage of patients remain on axitinib, and no new important safety signals were observed. Clinical trial information: NCT00835978