Background: JCOG1113 (UMIN000001685) is a randomized phase III trial in patients (pts) with advanced biliary tract cancers (BTCs) that shows the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) regarding overall survival (OS). Previous reports suggest that a history of major hepatectomy (MH) may affect dose intensity and adverse event (AE) frequency and reduce treatment efficacy in chemotherapy due to impairment of liver function and drug metabolism. We thus investigated whether a history of MH affects the frequency of AEs and treatment efficacy in recurrent BTC pts in JCOG1113. Methods: Among the 354 pts enrolled in JCOG1113, 76 recurrent pts with recurrence after surgery were included in this analysis. We compared the frequency of AEs, progression-free survival (PFS), and OS of GC vs. GS in pts treated with MH vs. non-major hepatectomy (NMH). Results: Of the 76 pts, 17 on GC and 13 on GS were included in the MH group, while 20 on GC and 26 on GS were included in the NMH group. The primary sites were only intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma in the MH group, and there were no differences between the groups regarding sex, performance status, biliary drainage, or site of recurrence. The hazard ratio (HR) of GS to GC for PFS was 0.74 (95% CI 0.35–1.56) in the MH group and 0.97 (95% CI 0.52–1.82) in the NMH group. The hazard ratio (HR) of GS to GC for OS was 0.99 (95% CI 0.418–2.36) in the MH group and 1.17 (95% CI 0.59–2.33) in the NMH group. The median PFS and OS for GS in the MH group were 12.2 months and 21.5 months. These were longer than the 6.8 months and 15.1 months in the original results for GS in JCOG1113. Regarding AEs, Grade 3-4 AEs, specifically neutrophil count decreased (73.1%/92.3%), platelet count decreased (3.9%/15.4%), and rash (7.7%/15.4%), were more common in MH pts than NMH pts on GS. On GC, AEs in the MH and NMH pts did not show any consistent trends. The relative dose intensities (RDIs) of gemcitabine (70.7%/62.5%) and S-1 (70.4%/54.5%) were lower in MH pts than NMH pts on GS. The RDIs of gemcitabine (67.4%/63.0%) and cisplatin (73.6%/65.0%) were slightly lower in MH pts than NMH pts on GC. Conclusions: For pts with a history of MH, some AEs increased, and the RDIs were lower, especially that of S-1 for GS. On the other hand, the HR for PFS suggests that GS may be more effective than GC in MH pts.