Aim S‐1 combined with cisplatin is known to be noninferior to taxanes plus platinum as the first‐line treatment for patients with advanced nonsmall cell lung cancer (NSCLC) in the Japanese population. This study aimed to evaluate the efficacy and safety profiles of oral S‐1 plus cisplatin (SP) in Taiwanese patients. Methods Patients with previously untreated stage IIIB or IV NSCLC were prospectively recruited to receive 40‐60 mg of S‐1 twice daily on days 1‐21 plus 60 mg/m2 of cisplatin on day 8 in a 5‐week cycle for up to six cycles. Results A total of 55 patients from five cancer centers in Taiwan were enrolled. Among the 46 evaluable patients, those administered with SP achieved disease control rate of 69.6% (partial response, 19.6%; stable disease, 50.0%), with median overall survival and progression‐free survival (PFS) of 15.1 and 5.7 months, respectively. Moreover, a better survival trend was observed in epidermal growth factor receptor mutation‐positive patients versus mutation‐negative patients treated with SP (PFS, 8.6 vs 5.6 months). The most commonly observed treatment‐related adverse events (AEs) were nausea (41.8%), followed by decreased appetite, anemia, and diarrhea. Grade of ≥3 AEs related to the study treatment occurred in 11 patients (20.0%). No febrile neutropenia or treatment‐related death was found in this study. Conclusions This study demonstrated that SP is an effective and safe first‐line regimen for Taiwanese patients with advanced NSCLC.