Background: Patients receiving the 5-mg twice daily (BID) axitinib starting dose exhibit variable drug exposure; prior pharmacokinetic analyses indicate higher exposure is associated with better outcomes in mRCC. Dose titration based on individual tolerability may optimize exposure and improve efficacy. Methods: Patients (N=213) with treatment-naïve mRCC received axitinib 5 mg BID for a 4-week lead-in period. Then, patients with 2 consecutive weeks of blood pressure ≤150/90 mmHg, no axitinib-related toxicities >grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized (double-blind) to axitinib 5 mg BID + dose titration to 10 mg BID maximum with axitinib or placebo. Those not eligible for randomization continued axitinib 5 mg BID or lower. Primary endpoint was objective response rate (ORR) in randomized arms. Progression-free survival (PFS), overall survival, and safety were secondary endpoints. Assuming response rate under the null hypothesis is 0.15, this study had ≥80% power (1-sided type I error 10%) to detect a ≥25% absolute improvement in ORR with active vs placebo titration. Results: In all, 56 patients each were randomized to active and placebo titration arms, 91 were not randomized, and 10 withdrew during the lead-in period. As of Oct 12, 2012, ORR (95% confidence interval [CI]) was 54% (40–67) in the active titration arm vs 34% (22–48) in the placebo titration arm (1-sided P=0.019), and 59% (49–70) in the non-randomized arm. Median PFS (95% CI) from first dose was 14.5 mo (9.2–24.5) in the active titration arm vs 15.7 mo (8.3–19.4) in the placebo titration arm (hazard ratio favored active titration, 0.85; 95% CI, 0.54–1.35; 1-sided P=0.244), and 16.6 mo (11.2–22.5) in the non-randomized arm. Most frequent all-grade, all-causality adverse events in active titration, placebo titration, and non-randomized arms, respectively, were diarrhea (61% vs 63% vs 63%), hypertension (61% vs 43% vs 82%), and fatigue (45% vs 46% vs 54%). Conclusions: Axitinib is effective and well tolerated in first-line mRCC with prolonged median PFS in all treatment arms compared to historical controls. Axitinib dose titration significantly improved ORR vs placebo. Clinical trial information: NCT00835978.