This study evaluated the efficacy and safety of nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck who had progressed after platinum-based chemotherapy. In a randomized, open-label, phase 3 trial, 361 patients were assigned to receive nivolumab (3 mg/kg every 2 weeks) or standard single-agent therapy (methotrexate, docetaxel, or cetuximab). The primary endpoint was overall survival, with additional endpoints including progression-free survival, response rate, safety, and quality of life. The median overall survival was 7.5 months with nivolumab versus 5.1 months with standard therapy, with a significant hazard ratio of 0.70 (P = 0.01). The 1-year survival rate was 36.0% with nivolumab and 16.6% with standard therapy. The median progression-free survival was 2.0 months with nivolumab and 2.3 months with standard therapy, but the difference was not statistically significant. The response rate was 13.3% with nivolumab and 5.8% with standard therapy. Treatment-related adverse events were less frequent and severe with nivolumab. Patient-reported quality of life measures remained stable or improved with nivolumab, while they worsened with standard therapy. Exploratory analyses suggested that nivolumab may be particularly effective in patients with higher PD-L1 expression or p16-positive tumors. In conclusion, nivolumab significantly improved survival and maintained quality of life compared to standard therapy in patients with platinum-refractory squamous-cell carcinoma of the head and neck.This study evaluated the efficacy and safety of nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck who had progressed after platinum-based chemotherapy. In a randomized, open-label, phase 3 trial, 361 patients were assigned to receive nivolumab (3 mg/kg every 2 weeks) or standard single-agent therapy (methotrexate, docetaxel, or cetuximab). The primary endpoint was overall survival, with additional endpoints including progression-free survival, response rate, safety, and quality of life. The median overall survival was 7.5 months with nivolumab versus 5.1 months with standard therapy, with a significant hazard ratio of 0.70 (P = 0.01). The 1-year survival rate was 36.0% with nivolumab and 16.6% with standard therapy. The median progression-free survival was 2.0 months with nivolumab and 2.3 months with standard therapy, but the difference was not statistically significant. The response rate was 13.3% with nivolumab and 5.8% with standard therapy. Treatment-related adverse events were less frequent and severe with nivolumab. Patient-reported quality of life measures remained stable or improved with nivolumab, while they worsened with standard therapy. Exploratory analyses suggested that nivolumab may be particularly effective in patients with higher PD-L1 expression or p16-positive tumors. In conclusion, nivolumab significantly improved survival and maintained quality of life compared to standard therapy in patients with platinum-refractory squamous-cell carcinoma of the head and neck.