Abstract Purpose: The addition of cytotoxic chemotherapy to immune-checkpoint inhibitor (ICI) may enhance antitumor effects. We conducted an open-label randomized phase II/III study to evaluate nivolumab + docetaxel combination therapy in comparison with nivolumab monotherapy for previously treated ICI-naïve non–small cell lung cancer (NSCLC). Patients and Methods: The primary endpoint of the phase III study was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and toxicity. As ICI and platinum-doublet combination chemotherapy was approved in the first-line setting during this study, patient accrual was discontinued. Results: One hundred twenty-eight patients (each arm, n = 64) were included in the full analysis set. The median OS in nivolumab (arm A) and nivolumab + docetaxel (arm B) was 14.7 months (95% CI, 11.4–18.7) and 23.1 months (95% CI, 16.7–NR), respectively. The HR for OS was 0.63 (90% CI, 0.42–0.95; P = 0.0310). The median PFS in arms A and arm B was 3.1 months (95% CI, 2.0–3.9) and 6.7 months (95% CI, 3.8–9.4), respectively. The HR for progression was 0.58 (95% CI, 0.39–0.88; P = 0.0095). The ORR was 14.0% (95% CI, 6.3–25.8) in arm A and 41.8% (95% CI, 28.7–55.9) in arm B. Hematotoxicity and gastrointestinal adverse events were more common in arm B than in arm A. Two treatment-related deaths were observed, including one patient in arm A who died of pneumonitis and one in arm B who died of myocarditis. Conclusions: Despite a slightly elevated toxicity, the addition of docetaxel to nivolumab has significantly prolonged the OS and PFS of patients with previously treated ICI-naïve NSCLC.