Background: In a phase 3 trial, nab-paclitaxel significantly improved progression-free survival (PFS) compared with DTIC (4.8 vs 2.5 months; hazard ratio [HR] 0.792; P = 0.044) in chemotherapy-naive patients with metastatic melanoma thereby meeting the primary study endpoint. A trend toward improved overall survival (OS; HR 0.831; P= 0.094) at the interim analysis (64% of patients with an event) was also shown. Here we report the final OS analysis. Methods: 529 patients with chemotherapy-naive, stage IV melanoma (M1c, 65%; elevated lactate dehydrogenase [LDH], 28%) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomized to receive nab-paclitaxel 150 mg/m² on days 1, 8, and 15 of a 28-day cycle (n = 264) or DTIC 1000 mg/m² on day 1 of each 21-day cycle (n = 265). The randomization was stratified by metastatic stage, region, and baseline LDH. BRAF status was known in 67% of patients; of these, 37% had mutant and 63% had wild-type BRAF melanoma. September 20, 2013, was the clinical cutoff date for the final OS analysis. Results: At the final OS analysis (median follow-up, ≈ 30 months for censored patients), 427 patient deaths occurred: 215 (81%) in the nab-paclitaxel vs 212 (80%) in the DTIC arm. Median OS trended in favor of nab-paclitaxel, but did not reach statistical significance vs DTIC (12.6 vs 10.5 months; HR 0.897;95% CI 0.738 - 1.089; P = 0.271. OS favored nab-paclitaxel vs DTIC across most patient subgroups, including patients aged ≥ 65 years and those with M1c stage disease, elevated LDH, and any BRAF status melanoma. The use of poststudy anticancer therapy did not differ by treatment arm, with 77% vs 73% of patients in the nab-paclitaxel arm vs DTIC arm receiving poststudy therapy. The use of a BRAF inhibitor (13% vs 10%) or ipilimumab (31% vs 32%) was also similar between treatment arms. As previously reported, the most common grade ≥ 3 adverse events with nab-paclitaxel were peripheral neuropathy (25% vs 0% with DTIC) and neutropenia (20% vs 10% with DTIC). Conclusions: The study met the primary endpoint with a significant improvement in PFS. At final analysis, nab-paclitaxel continued to demonstrate a trend toward improved OS vs DTIC. Clinical trial information: NCT00864253.