BACKGROUND After decades of research, pancreatic cancer is still a devastating disease. The aim of this article was to assess the efficacy and safety of combination chemotherapy with gemcitabine (GEM) and S-1 (GS) therapy compared with GEM alone therapy in patients with locally advanced or metastatic pancreatic cancer. METHODS Relevant trials were identified by searching databases. Five trials were selected in this article. The indicators we used were overall response rate, disease control rate, 1-year survival rate and haematological toxicities. RESULTS Meta-analysis of the pooled data demonstrated that the overall response rate (risk ratio, RR = 2.52, 95% confidence interval, CI: 1.85-3.42, P < 0.00001) and disease control rate (RR = 1.24, 95% CI: 1.12-1.37, P < 0.0001) were significantly different for the GS and GEM alone chemotherapies. Among the group of patients, 43.4% in the GS group and 31.4% in the GEM group survived more than a year. According to this, patients who use the GS regiment may have a better prognosis than the GEM regiment (RR = 1.62, 95% CI: 1.12-2.33, P = 0.04). The combination chemotherapy with GEM and S-1 group had higher haematological toxicities including neutropaenia (RR = 1.58, 95% CI: 1.17-2.14, P = 0.003) and thrombocytopaenia (RR = 1.85, 95% CI: 1.28-2.67, P = 0.001). The incidence of anaemia was much the same in the two groups (RR = 1.22, 95% CI: 0.87-1.70, P = 0.24). CONCLUSIONS Overall response rate and disease control rate as well as 1-year survival rate in patients who received GS were superior to those treated with GEM alone. Combination chemotherapy with GEM and S-1 may offer greater benefits in the treatment of pancreatic cancer than GEM alone, although the GS group had higher haematological toxicities. Combination chemotherapy with GEM and S-1 might be an option of first-line chemotherapy for pancreatic cancer patients, at least in Asia. Mini Abstract: This systematic review analysing randomized controlled trials (RCTs) comparing S-1 combination chemotherapy versus GEM alone for locally advanced and metastatic pancreatic cancer demonstrated greater efficacy for S-1 combination in term of response, disease control and 1-year survival proportion.