Abstract: Objective To investigate the efficacy and toxicity of S-1 plus oxaliplatin versus S-1 plus cisplatin as the first-line treatment for elderly patients with advanced gastric cancer. Methods Fifty-six elderly patients with advanced gastric cancer were randomly divided into S-1 plus oxaliplatin group（SOX，n=30）and S-1 plus cisplatin group（SP，n=26）. In SOX group, S-1 was administered orally（4060mg，bid） from d1 to d14，and oxalipatin（130mg／m2）was administered intravenously on d1. Every 21 days was a cycle. In SP group，cisplatin was administered intravenously 25mg／m2 on d1-d3，and the administration of S-1 followed the same dosage as SOX group. Every 21 days was a cycle. Efficacy was evaluated every two cycles. Results The effective rates of SOX group and SP group were 46.7％ and 38.5％（P=0.596），the disease control rates were 80.0％ and 76.9％（P=1.000），the median progress-free survival were 6.0 months and 5.6 months（P=0.831），and the median overall survival were 123months and 11.5 months（P=0.401）.The main toxicity in the two groups was hematological toxicity，and the occurrence of grade 3-4 toxicity in SOX group and SP group had no difference. The nonhematological toxicity in the two groups was all in grade 1-2，and the main toxicity was peripheral neuritis in SOX group, while in SP group were abnormal renal function and nausea/vomitting. The improvement rate of KPS score in SOX group and SP group were 83.3％ and 46.2％（P=0.027），and the increased rate of FACT-G score were 76.7％ and 38.5％（P=0.006）. Conclusion Both SOX and SP regimen are effective for elderly patients with advanced gastric cancer. Compared with SP regimen， SOX regimen is better tolerated as the first-line treatment for advanced gastric cancer.