Background: Relapse after highly invasive surgery for biliary tract cancers (BTCs), especially in the early postoperative period, causes medical, psychological, social, and economic disadvantages to the patients. However, approximately 30% of patients with curatively resected BTCs experience relapse within the first 12 months. JCOG1202 (UMIN000011688) is a randomized phase III trial conducted in patients with resected BTCs showing the benefit of adjuvant S-1 for overall survival. This study aimed to investigate the risk factors for early relapse of resected BTCs in the JCOG1202 cohort. Methods: Of the 440 patients enrolled in the JCOG1202, 217 patients who received surgery alone (arm A) and 207 patients who received adjuvant S-1 (arm B) were eligible and included in this analysis. Early relapse was defined as relapse or death within 12 months after enrollment. Predictive factors for early relapse were assessed using logistic regression analyses. Results: Postoperative early relapse was observed in 59 (27.2%) and 38 (18.4%) of patients in arm A and arm B, respectively. In multivariable logistic regression analysis for the 424 eligible patients, postoperative CA19-9 levels >37 u/ml (odds ratio (OR): 2.790, 95% confidence interval (CI): 1.262-6.170), poorly differentiation (vs. well-differentiated/papillary) (OR: 4.746, 95% CI:1.927-11.688), moderate differentiation (vs. well-differentiated/papillary) (OR: 1.955, 95% CI:1.071-3.567), lymph node metastases > 4 (vs. 0) (OR: 3.991, 95% CI: 1.674-9.514), lymph node metastases 1-3 (vs. 0) (OR: 2.661, 95% CI: 1.471-4.814), and presence of residual tumor (OR: 2.171, 95% CI: 1.070-4.408) were independent risk factors for early relapse. Importantly, adjuvant S-1 chemotherapy significantly reduced early relapse (OR: 0.491, 95% CI: 0.290-0.833). Similar results were observed in arm B. Conclusions: Postoperative CA19-9 level, tumor differentiation, lymph node metastases, and the residual tumor significantly impact early relapse in patients with curatively resected BTCs. Although adjuvant S-1 chemotherapy was effective in reducing early relapse, similar factors tended to be the risk factors in patients receiving adjuvant S-1 chemotherapy. Patients at high risk of early relapse may need more intensive perioperative therapy. Clinical trial information: UMIN000011688.