Background: Most patients (pts) with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy (CT) alone in Japan. Chemoradiotherapy (CRT) is also a treatment option, but the role of radiotherapy (RT) remains controversial. Recently, induction CT followed by CRT is recognized as one potentially promising strategy. The aim of this study is to evaluate the efficacy and safety of CRT with and without induction CT to determine which is more promising CRT strategy. Methods: LAPC pts with an ECOG PS of 0-1, aged 20-80, and adequate organ function were randomized to CRT (Arm A) or induction CT followed by CRT (Arm B). Pts in Arm A received RT (50.4 Gy/28 fr over 5.5 weeks) with concurrent S-1 (40 mg/m²/dose, b.i.d. on the day of irradiation). Pts in Arm B received induction gemcitabine (GEM) (1,000 mg/m², iv, days 1, 8 and 15, every 4 weeks) for 12 weeks, and then, only pts with controlled disease received same CRT as Arm A. After CRT, GEM was continued until disease progression or unacceptable toxicity in both arms. Primary endpoint was overall survival (OS). The sample size was 100 to detect ≥10% difference in 1-year OS with a probability of at least 0.9. Arm B will be considered to be more promising if point estimate of hazard ratio (HR) of OS for Arm B to Arm A is smaller than 1.186. Results: From 12/2011 to 9/2013, 102 pts were randomized, but 2 pts were ineligible because of metastasis. Therefore, 100 pts (Arm A/B n=51/49) were evaluated in this analysis. 50 pts received CRT in Arm A, while 34 pts in Arm B. 1-year OS for Arm A/B were 66.7/69.3% (HR 1.16 [95%CI 0.71-1.89]; p=0.56), and 1-year PFS were 39.2/46.6% (HR 1.05 [0.68-1.61]; p=0.84). Incidences of grade 3/4 toxicities in Arm A/B were leukopenia 62/61%, neutropenia 54/57%, anemia 18/12%, thrombocytopenia 10/14%, anorexia 16/4%, fatigue 8/4%, nausea 8/2%, diarrhea 6/4%, gastroduodenal (GD) hemorrhage 8/6%, GD ulcer 6/4%, and biliary infection 20/27%. Two treatment-related deaths occurred in Arm A (pneumonitis, duodenal hemorrhage). Conclusions: Induction CT followed by CRT was considered more promising as the test arm for a subsequent phase III trial comparing with CT alone. Clinical trial information: 000006811.