Background: JCOG1202 (UMIN000011688) is a randomized phase III trial conducted in patients (pts) with biliary tract cancers (BTCs) that showed the superiority of adjuvant S-1, in terms of the overall survival (OS). Previous reports have suggested that major hepatectomy (MH) may affect the dose intensity as well as frequency of adverse events (AEs) and reduce the treatment efficacy of chemotherapy, due to impaired liver function and drug metabolism. Therefore, we investigated whether MH might affect the feasibility of adjuvant S-1 chemotherapy. Methods: Among the 440 pts enrolled in the JCOG1202 study, 207 pts who received adjuvant S-1 were included in this analysis. We compared the rate of treatment completion, the frequency of AEs, and the dose intensity of adjuvant S-1 after MH versus non-major hepatectomy (NMH). MH was defined as right hemi-hepatectomy, right trisectionectomy, left trisectionectomy, and central bi-sectionectomy, with or without pancreatoduodenectomy. Results: Of the 207 pts, 42 pts had undergone MH and 165 pts had undergone NMH. The primary cancers in the MH group were mainly intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. The pretreatment characteristics of the pts were as follows: performance status 0 (MH vs. NMH: 81.0% vs. 89.1%), biliary reconstruction (performed: 81.0% vs. 82.4%), time from hepatectomy to initiation of adjuvant S-1 therapy (median: 60 vs. 57 days), platelet count (17.7 vs. 23.4 x 10⁴/μL), and serum albumin (3.5 vs. 3.8 g/dL). The treatment completion proportion was lower in the MH group as compared to the NMH group (59.5% vs. 75.8%; treatment completion ratio, 0.786 (95% CI, 0.603-1.023), p = 0.0733), and the median dose intensity was lower in the MH group than in the NMH group (90% vs. 100%, p = 0.0358). The proportion of pts who discontinued adjuvant S-1 due to occurrence of AEs in the MH group vs. the NMH group was 23.8% vs. 10.3%. The major reasons for treatment discontinuation were biliary infection, nausea/vomiting, and diarrhea; these AEs were mainly observed in the first cycle; the frequency of grade 3-4 biliary infection during adjuvant S-1 therapy was 19.0% in the MH group versus 4.2% in the NMH group. Conclusions: In regard to adjuvant S-1 therapy for pts with resected BTC, the treatment completion proportion and dose intensity were lower in the MH group as compared to the NMH group. Caution should be exercised against the development of biliary infections during postoperative adjuvant S-1 therapy after MH in BTC pts.