Immune checkpoint blockade (ICB) has revolutionized outcomes for patients with melanoma across multiple disease settings. In patients with advanced, unresectable disease, the ICB combination of nivolumab (anti-PD1) and relatlimab (anti-LAG-3) has demonstrated improved clinical outcomes compared with nivolumab monotherapy. There exists an unmet need to identify biomarkers that predict response to this combination regimen and rational therapeutic strategies to overcome resistance. We previously reported the initial results of a phase II clinical trial (ClinicalTrials.gov identifier: NCT02519322) of neoadjuvant systemic treatment (NST) followed by adjuvant treatment with nivolumab and relatlimab, which achieved a major pathologic response (MPR; ≤10% viable tumor) rate of 63% in patients with stage III/IV, surgically resectable melanoma. Our updated clinical follow-up (median 47 months) for these patients demonstrates that at 4 years from the start of NST, 80% of patients remain event-free, including 95% of patients who achieved a MPR. Gene expression analysis of longitudinally collected biospecimens from the trial identifies baseline upregulation of several immune modulatory pathways associated with MPR; by contrast, increased B7-H3 expression was associated with resistance. This work demonstrates the long-term benefit of neoadjuvant nivolumab and relatlimab and identifies a potentially targetable predictor of resistance to this combination therapy.