Abstract: Objective:To comparatively analyze the efficacy of S-1 plus cisplatin as first-line chemotherapy between advanced AFP posi -tive and AFP negative gastric cancer. Methods:A total of 89eligible patients with advanced gastric cancer from January 2010to June 2013were enrolled in this retrospective study. The cases were divided into AFP positive group (n=18) and AFP negative group ( n=71) based on serum AFP level before treatment. Both groups received S-1 plus cisplatin as first-line treatment. Results:Significant differ -ences were observed in remission rate ( 66. 7% versus 32. 4% ,P=0. 028 ) and radical surgical resection rate ( 44. 5% versus 18. 3% ,P=0. 029 ) after chemotherapy between AFP positive group and AFP negative group. In the two groups, neither progression-free survival nor overall survival (OS) showed any significance ( P>0. 05) in patients without surgery after chemotherapy. However, the disease-free survival of the two groups with radical surgical resection after chemotherapy was significantly different (median: 27. 0 months versus 15. 6 months, P =0. 034 ). The OS of the AFP positive group was evidently longer than that of the AFP negative group (median: 16. 0 months versus 11. 0 months,P=0. 005 ). Conclusion: As first-line chemotherapy, S-1 plus cisplatin was more effective for the advanced AFP positive gastric cancer and prolonged overall survival.