Objective: There remains no standard first-line chemotherapeutic regimen for advanced gastric cancer (AGC). The aim of this study was to evaluate the efficacy and safety of combination regimen with weekly paclitaxel and S-1 as a firstline chemotherapy for AGC. Methods: Forty-six patients with AGC were included in this study. Paclitaxel was administered weekly at a dose of 60 mg/m2 on days 1, 8 and 15, S-1 was administered orally twice daily at 80 mg/m2/day for 2 weeks. The regimen was repeated every four weeks. Results: The results showed that the overall response rate was 45.7%, with 3 patients achieved complete response and 18 patients had a partial response, the disease control rate was 76.1%. The median progress free survival was 7.2 months [95% confidence interval (CI): 6.3–8.1 months] and the median overall survival was 11.6 months (95% CI: 10.6–12.6 months) after treatment with paclitaxel and S-1. Neutropenia occurred in 25 patients (54.3%) and grade 3/4 neutropenia was observed in 8 patients (17.4%), gastrointestinal reactions were the most common non-hematologic toxicities, while severe gastrointestinal toxicities were uncommon. Conclusion: The regimen of weekly paclitaxel and S-1 demonstrated activity and acceptable toxicity for AGC as a first-line chemotherapy.