Background: In phase 2/3 randomized RELATIVITY-047, nivolumab plus relatlimab demonstrated a statistically significant improvement in progression-free survival (PFS), a clinically meaningful but not statistically significant improvement in overall survival (OS), and a numerically higher objective response rate (ORR) versus nivolumab alone in patients with previously untreated advanced melanoma. Methods: Descriptive 4-year updated analyses in patients treated with nivolumab 480 mg plus relatlimab 160 mg fixed-dose combination versus nivolumab 480 mg intravenously every 4 weeks are presented. Primary endpoint was PFS by blinded independent central review (BICR). Other endpoints included melanoma-specific survival (MSS). Results: At 45.3 months' minimum follow-up, nivolumab plus relatlimab versus nivolumab PFS improvement was maintained: 4-year PFS rates were 30.6 % (95 % CI, 25.4–35.9) versus 23.6 % (95 % CI, 18.9–28.5); OS was numerically better with 4-year OS rates of 52.0 % (95 % CI, 46.6–57.1) versus 42.8 % (95 % CI, 37.5–47.9); and ORR difference was maintained at 43.9 % (95 % CI, 38.7–49.3) versus 33.4 % (95 % CI, 28.6–38.6), respectively. 4-year MSS rates were 59.7 % (95 % CI, 54.1–64.8) for nivolumab plus relatlimab and 49.6 % (95 % CI, 44.0–54.9) for nivolumab. Efficacy across the majority of prespecified subgroups favored the combination. No new or unexpected safety signals were identified. Conclusions: With 4 years of follow-up, nivolumab plus relatlimab demonstrated durable improvement in outcomes versus nivolumab monotherapy for patients with previously untreated advanced melanoma. The durable benefit observed comes at a lower toxicity cost compared with other immuno-oncology combinations. Trial registration: ClinicalTrials.gov Identifier: NCT03470922