Abstract Neoadjuvant ipilimumab plus nivolumab has become standard therapy for stage III melanoma based on the NADINA trial, though long-term data are lacking. In the phase 2 PRADO cohort of OpACIN-neo (NCT02977052), 99 patients with stage III macroscopic melanoma received this regimen. We report first-time 5-year survival data: 71% event-free survival, 74% relapse-free survival, 79% distant metastasis-free survival, and 86% overall survival. Ongoing grade 1-2 immune-related adverse events occurred in 69% of patients alive, predominantly vitiligo and hypothyroidism. Major pathologic response (MPR), high tumor mutational burden (TMB), high interferon-gamma signature (IFNg), and PD-L1 expression ≥1% were associated with favorable outcomes. Combined high TMB, IFNg, and PD-L1 expression yielded 100% MPR and 100% 5-year event-free survival, while triple low expression had only 18% MPR and 41% event-free survival. Our findings demonstrate favorable long-term outcomes for patients with an MPR and identify TMB, IFNg, and PD-L1 as promising baseline biomarkers.