AIM:To assess the efficacy and safety of combination therapy based on S-1,a novel oral fluoropyrimidine,vs S-1 monotherapy in advanced gastric cancer(AGC).METHODS:We searched PubMed,EMBASE and the Cochrane Library for eligible studies published before March 2013.Our analysis identified four randomized controlled trials involving 790 participants with AGC.The outcome measures were overall survival(OS),progression-free survival(PFS),overall response rate(ORR)and grade 3-4 adverse events.RESULTS:Meta-analysis showed that S-1-based combination therapy significantly improved OS(HR=0.77,95%CI:0.66-0.91,P=0.002),PFS(HR=0.58,95%CI:0.46-0.72,P=0.000)and ORR(OR=2.23,95%CI:1.54-3.21,P=0.000).Sensitivity analysis further confirmed this association.Lower incidence of grade 3-4 leucopenia(OR=4.06,95%CI:2.11-7.81),neutropenia(OR=3.94,95%CI:2.1-7.81)and diarrhea(OR=2.41,95%CI:1.31-4.44)was observed in patients with S-1 monotherapy.CONCLUSION:S-1-based combination therapy is superior to S-1 monotherapy in terms of OS,PFS and ORR.S-1 monotherapy is associated with less toxicity.