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 89 eligible patients with advanced gastric cancer from January 2010 to June 2013 were 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.