Objective To compare the efficacy and side effects of S-1 combined with oxaliplatin and capecitabine combined with oxaliplatin in treatment of advanced gastric cancer. Methods From Mar 2011 to Dec 2014, the data of 93 cases with gastric cancer in Zhengzhou Peopleˊs Hospital were studied retrospectively. 48 cases treated by S-1 combined with oxaliplatin (SL group) and 45 cases treated by capecitabine combined with oxaliplatin (XL group). The patients of SL group received S-1 80 mg·m-2·d-1, bid, po, d1-14, L-OHP 130 mg/m2, ivgtt, 2 hours, d1. The patients of XL group received capecitabine 2 000 mg·m-2·d-1, bid, po, d1-14, L-OHP 130 mg/m2, ivgtt, 2 hours, d1. The course was 21 days in two groups. The efficacy and side effects were evaluated after two courses. Results The efficacy rates of SL and XL group were 52.08 % (25/48) and 53.33 % (24/45), respectively there was no significant difference (P > 0.05). The incidence rate of gastrointestinal reaction in SL group was obviously higher than that in XL group [52.08%(25/48) vs 24.44%(11/45), P<0.05]. The incidence rate of oral mucositis in SL group was significantly lower than that in XL group [25.00 % (12/48) vs 51.11 % (23/45), P< 0.05]. Conclusion Both S-1 combined with L-OHP and capecitabine combined with L-OHP for gastric cancer treatment are safe and effective.