This study evaluated the safety and clinical activity of combining nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in advanced melanoma patients. Fifty-three patients received the concurrent regimen (nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses), and 33 received the sequenced regimen (nivolumab after ipilimumab). The objective response rate was 40% in the concurrent regimen group, with 65% showing evidence of clinical activity. At the maximum tolerated dose (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 53% achieved an objective response, all with ≥80% tumor reduction. Grade 3–4 adverse events occurred in 53% of patients, but were generally manageable and reversible. In the sequenced regimen group, 18% had grade 3–4 adverse events, and the objective response rate was 20%. The combination demonstrated a manageable safety profile and achieved clinical activity distinct from monotherapy, with rapid and deep tumor regressions in a substantial number of patients. These results support further investigation of this combination in a randomized phase 3 trial.This study evaluated the safety and clinical activity of combining nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in advanced melanoma patients. Fifty-three patients received the concurrent regimen (nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses), and 33 received the sequenced regimen (nivolumab after ipilimumab). The objective response rate was 40% in the concurrent regimen group, with 65% showing evidence of clinical activity. At the maximum tolerated dose (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 53% achieved an objective response, all with ≥80% tumor reduction. Grade 3–4 adverse events occurred in 53% of patients, but were generally manageable and reversible. In the sequenced regimen group, 18% had grade 3–4 adverse events, and the objective response rate was 20%. The combination demonstrated a manageable safety profile and achieved clinical activity distinct from monotherapy, with rapid and deep tumor regressions in a substantial number of patients. These results support further investigation of this combination in a randomized phase 3 trial.