Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients with advanced NSCLC previously treated with >= 1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m(2) in Japan, 75 mg/m(2) at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. Japan Pharmaceutical Information Center, JapicCTI-101155.