Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase 1/2 data show activity of nivolumab in previously treated SCLC.CheckMate 331 is a randomized, open-label, phase 3 trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line platinum-based chemotherapy were randomized 1:1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy (median OS, 7.5 vs 8.4 months; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.72-1.04; P = 0.11). A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab vs chemotherapy) was similar in patients with programmed death ligand 1 combined positive score ≥ 1% versus < 1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.