Objective: The purpose of the study was to compare the clinical efficacy and adverse effect of S-1 alone and gemcitabine alone in elderly patients with advanced pancreatic cancer. Methods: A total of 44 elderly patients with advanced pancreatic cancer were included in the study, who received S-1 alone (n=21) or gemcitabine alone (n=23). RECIST was used to assess the efficacy of the treatment and NCI CTC-AE version was used to describe adverse events. Results: There was no statistically significant difference in the objective response rate (ORR) and the disease control rate (DCR) between the two groups (P>0.05). The median progression-free survival (PFS) was 3.6 months in S-1 group and 4.0 months in gemcitabine group, which had no statistically significant difference (P>0.05). The drug-related neutropenia in S-1 group was lower than in gemcitabine group, which had statistically significant difference (P=0.01). Other drug-related adverse events were gastrointestinal response and abnormal liver function most of witch were grade 1 to 2. Conclution: S-1 may be recommended as first-line chemotherapy for elderly patients with advanced pancreatic cancer because of its safety, efficacy and convenience, especially for elderly patients with PS 2 who could not tolerate gemcitabine or other combination programmes.