Background: The phase III trial (JCOG1104), comparing between 4- (6 months) and 8-course (1 year) of S-1 as the adjuvant chemotherapy for pathological stage II gastric cancer, registered a total of 590 patients between Feb. 2012 and Mar. 2017 until the study was terminated due to futility at the interim analysis (relapse-free survival at 3 years: 93.1% in the 8-course group and 89.8% in the 4-course group). Non-inferiority of the 4-course to the 8-course was not shown, highlighting a continuation of S-1 adjuvant chemotherapy for one year. This preplanned exploratory study investigated the risk factors for time to treatment failure (TTF). Methods: TTF was defined as the time from randomization to the date of termination of S-1 before the planned treatment period, relapse, or any cause of death, whichever came first, and censored on the last date of contact for a surviving patient after completing the planned treatment or the last date of S-1 in the patients under the protocol treatment when the trial was closed. The risk factor of TTF was analyzed by Cox proportional hazard model using the variables of the planned treatment period, PS, age, sex, body weight loss (percentile of the body weight loss at the registration compared with that before surgery: BWL), albumin, lymphocyte count, creatinine clearance (Ccr), extent of gastrectomy (total gastrectomy vs. others), surgical approach (open vs. laparoscopic approach), and blood loss during surgery. As TTF did not reach 50%, proportion of treatment completion was compared. Results: Among 590 registered patients, this study included 530 patients (273 in the 8-course group and 257 in the 4-course group) by excluding 24 ineligible patients, 7 patients who did not start the protocol treatment, and 29 patients with unavailable data for variables. Proportion of treatment completion at 6 months estimated by Kaplan-Meier method were 89.2% in the 4-course group and 84.6% in the 8-course group (P=0.1204), and that at 1 year was 73.6% in the 8-course group. Risk factors of TTF before 6M identified by multivariable analysis with stepwise selection method including both groups, in which all patients completed treatment were censored at 6 months, were the planned treatment period (4-courses vs. 8-course, HR 0.611, 95% Confidence interval (CI) 0.375-0.996, P=0.0482), age (continuous value, HR 1.039, 95% CI 1.004-1.074, P=0.0266), and Ccr (<80 vs. >80 ml/min, HR 1.943, 95% CI 1.105-3.415, P=0.0211). As for the TTF in the 8-course group, BWL (>10% vs <10%, HR 2.167, 95% CI 1.269-3.703, P=0.0046) and Ccr (<80 vs. >80 ml/min, HR 1.900, 95% CI 1.186-3.045, P=0.0076) were independent risk factors. Conclusions: Compared to 8-course, 4-course of S-1 adjuvant chemotherapy was associated with a higher 6-month proportion of treatment completion. When planning the adjuvant chemotherapy with S-1 for one year, BWL (>10%) and low Ccr (<80 ml/min) were risk factors for treatment failure. Clinical trial information: UMIN000007306.