Objective To evaluate the efficacy and toxicity of the combination of S-1 and oxaliplatin in the first-line chemotherapy of patients with advanced gastric cancer. Methods From March 2012 to April 2013, 57 patients in the First Affiliated Hospital of Guangxi Medical University were enrolled in this study. Oxaliplatin was administered at 130 mg/m2 on day 1, while S-1 was administered orally (< 1.25 m2: 40 mg twice per day; 1.25-1.50 m2: 50 mg twice per day; > 1.50 m2: 60 mg twice per day) for 14 days. The response was evaluated every two chemotherapy cycles. Results The objective response rate was 52.6%, and the disease control rate was 84.2%. The median time to progression was 5.8 months, and the median survival time was 13.5 months. The major grade 3/4 hematological toxic effects were neutropenia (12.3%) and thrombocytope nia (12.3%), and the grade 3/4 non-hematological toxic effects were vomiting, fatigue and sensory neuropathy. The rate of clinical benefit response was 71.9% (41/57). Conclusion The regimen of oxaliplatin and S-1 shows precise efficacy and good tolerance against advanced gastric cancer, and it is worthy of promotion and application in the future.