Objective: To assess the efficacy of pancreaticoduodenectomy (PD) followed by tegafur/gimeracil/oteracil (S-1) adjuvant chemotherapy in treatment of pancreatic cancer. Methods: Between February 2008 and June 2011, 58 patients with stage I-II pancreatic cancer underwent PD followed by postoperative adjuvant chemotherapy with S-1 (32 cases, observational group) or gemcitabine (26 cases, control group). The short- and long- term efficacies as well as the incidence of adverse events during chemotherapy between the two groups of patients were compared. Results: The levels of serum tumor markers in both groups of patients were significantly decreased after chemotherapy compared with their levels before chemotherapy (all P<0.05), but showed no significant difference between the two groups (all P>0.05); the overall response rate in observational group was significantly higher than that in control group (37.50% vs. 30.77%, P<0.05); survival analysis showed that the 1-, 1.5- and 2-year overall survival rate in observational group were significantly higher than those in control group (all P<0.05); the adverse reactions in either group were grade I or II, and there was no significant difference in incidence of adverse reactions between the two groups (P>0.05). Conclusion: PD plus postoperative S-1 adjuvant chemotherapy for pancreatic cancer patients has proven efficacy, which may effectively prolong the postoperative survival time of the patients, with only mild adverse effects, and good tolerance.