BACKGROUND Gemcitabine and S-1 are drugs commonly used for treating locally advanced pancreatic cancer (LAPC). However, the safety and efficacy of combination of these agents for induction chemotherapy (IC) followed by chemoradiotherapy are not well-defined. PATIENTS AND METHODS Fifteen patients with LAPC (IC-CRT group) were treated with gemcitabine and S-1 IC, followed by S-1 chemoradiotherapy. The clinical outcomes were compared to a cohort of 38 patients who received chemoradiotherapy alone (CRT group). RESULTS Disease control rates in the CRT and IC-CRT groups were 84% and 93%, respectively (p=0.024). The median time of disease progression was 10.8 and 15.4 months in the CRT and IC-CRT group, respectively (p=0.043). The median overall survival time was longer in the IC-CRT group compared to CRT (23.4 vs. 17.3 months), but this increase was not statistically significant. CONCLUSION Gemcitabine and S-1 combination chemotherapy, followed by CRT, is a promising IC regimen for treating LAPC.