Durable responses and encouraging survival have been demonstrated with immune checkpoint inhibitors in small-cell lung cancer (SCLC), but predictive markers are unknown. We used whole exome sequencing to evaluate the impact of tumor mutational burden on efficacy of nivolumab monotherapy or combined with ipilimumab in patients with SCLC from the nonrandomized or randomized cohorts of CheckMate 032. Patients received nivolumab (3 mg/kg every 2 weeks) or nivolumab plus ipilimumab (1 mg/kg plus 3 mg/kg every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks). Efficacy of nivolumab ± ipilimumab was enhanced in patients with high tumor mutational burden. Nivolumab plus ipilimumab appeared to provide a greater clinical benefit than nivolumab monotherapy in the high tumor mutational burden tertile. •This study evaluated the role of tumor mutational burden (TMB) in SCLC•Efficacy of nivolumab with or without ipilimumab increases with higher TMB in SCLC•The benefit of nivolumab plus ipilimumab is greatest in patients with high-TMB SCLC•TMB has a potential role as a biomarker for immunotherapy across lung cancers Hellmann et al. evaluate the impact of tumor mutational burden on the efficacy of nivolumab monotherapy or combination with ipilimumab in patients with small-cell lung cancer (SCLC). They show that treatment efficacy and the increased benefit of the combination are most substantial in SCLC with high tumor mutational burden.