Background: We previously reported the results of the JCOG0205 study, which indicated that D2/D3 lymph node dissection followed by adjuvant fluoropyrimidine (F) monotherapy resulted in better disease-free survival (DFS) and overall survival (OS) in Japan than in Western countries (EJC 2014). Cape is one of standard adjuvant chemotherapy for stage III CC (NEJM 2005). Recently, S-1 was demonstrated to be non-inferior to uracil and tegafur plus leucovorin in DFS (Ann Oncol 2014). This is the first report of JCOG0910, which compared S-1 with cape. Methods: Key eligibility criteria were: stage III, colorectal adenocarcinoma except for lower rectal cancer, R0 with D2/3 lymph node dissection, 20-80 years old. Patients were randomized to 8 courses of cape (2,500 mg/m²/day, days 1–14, q3w) or 4 courses of S-1 (80 mg/m²/day, days 1–28, q6w). Primary endpoint was DFS. Planned sample size was 1,550 to provide 80% power with a non-inferiority margin of hazard ratio (HR) of 1.24 and 1-sided α = 0.05; with interim analyses after 50% of the planned accrual and 1 year after completion of accrual. Results: Between Mar 2010 and Aug 2013, 1,564 pts were randomized to cape (n = 782) or S-1 (n = 782). Median age was 66; male/female: 52%/48%, colon/rectum: 68%/32%, number of positive nodes ≤ 3/4 ≤ : 84%/16%. At the second interim analysis on Sep 2014, 48% of required events (258/535) were observed, and JCOG Data and Safety Monitoring Committee recommended early publication because S-1 was apparently inferior to cape in DFS. With median follow-up of 23.7 months for all randomized pts, 3-year DFS was 82.0% in cape and 77.9% in S-1. The HR of DFS was 1.23 (99.05% CI, 0.887–1.70) and the non-inferiority of S-1 was not demonstrated (P = 0.111). The incidence of grade 3/4 adverse events was 21.2% in cape and 12.1% in S-1. Hand-foot syndrome was common in cape, whereas diarrhea and anorexia were common in S-1. Conclusions: This study failed to demonstrate the non-inferior of adjuvant S-1 to cape in DFS. Adjuvant cape remains the standard treatment and S-1 should not be used for stage III CC. Clinical trial information: UMIN000003272.