We aimed to evaluate the efficacy and safety of combination chemotherapy with S-1 and low-dose weekly cisplatin in patients with advanced non-small cell lung cancer (NSCLC). In this phase II trial, previously untreated patients with stage IIIB/IV NSCLC were treated with oral administration of S-1 at 80 mg/m(2) for 21 days and three consecutive weekly low doses of cisplatin (25 mg/m(2)) followed by a 2-week rest period. Twenty-six patients were eligible for the assessment of efficacy and safety. Six partial responses were observed with an overall response rate of 23.1% (95% confidence interval: 12.3-31.6%). The median survival time and median progression-free survival were 13.4 months and 5.4 months, respectively. Grade 3/4 hematologic toxicities were observed in 9 patients (34.6%), including one grade 4 neutropenia and thrombocytopenia. As for non-hematologic adverse reactions, although grade 3 events were observed in 4 patients (15.3%), no severe renal toxicity or vomiting was found. S-1 and weekly low-dose cisplatin combination chemotherapy in patients with advanced NSCLC showed an acceptable response rate, overall survival time, and toxicity. Because this regimen can be performed in an outpatient setting, it might be an alternative useful and convenient option. Further investigations with a large population are required to confirm our results.