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Background Homologous recombination deficiency (HRD) occurs when tumor cells lack the ability to repair double-strand DNA breaks via the homologous recombination repair pathway, often due to mutations in genes such as BRCA, ATM. HRD has emerged as a potential biomarker for treatment response in various cancers. However, the role of HRD status in predicting benefit from the addition of IO to CT in BTC remains poorly understood. This study evaluated progression-free survival (PFS), and overall survival (OS) associated with CIO vs. CT alone in patients(pts) with HRD-positive (+) and HRD-negative (-) BTC.Methods A multicenter retrospective cohort study was conducted, including 998 pts with advanced BTC treated from 2012-2024 across Japan, the U.S., and Brazil. HRD status was determined via tissue or blood-based genomic sequencing and pts were grouped by treatment received (CT vs. CIO). Primary endpoints were PFS and OS, assessed using Kaplan-Meier and Cox proportional hazards models.Results Of 998 patients, 819 (82%) were HRD-, and 179 (18%) were HRD+. CIO was administered to 120 pts (12%) as 1L therapy, while 888 pts (89%) received CT only. Median age was 66 years. Among HRD+ pts, the most frequently altered genes were ATM (38.5%), BRCA2 (23.5%), BRCA1 (16.2%), and CHEK2 (8.9%). In HRD- pts, OS was 16.9 months(mos) with CIO vs. 17.9 mos with CT (HR 0.92; p=0.61); PFS was 6.8 mos with CIO versus 6.0 mos with CT alone (HR 0.84; p=0.17). In HRD+ pts treated with CIO vs those who received CT alone were 13.4 vs. 22.5 mos respectively (HR 2.07; p=0.006); PFS was 6.0 mos with CIO and 7.0 mos with CT (HR 1.39; p=0.13). We observed a significant OS advantage for HRD+ pts treated with CT than HRD- pts (22.5 vs. 17.9 mos; HR 0.74; p=0.012). Additionally, HRD status was not independently prognostic (HR 0.92; p=0.35), and the addition of IO was not independently associated with improved OS (HR 0.94; p=0.58).Conclusions HRD+ status seems to predict the lack of benefit from the addition of IO to CT in patients with BTC. The addition of IO to CT did not significantly improve survival outcomes over CT alone in either the HRD+ or HRD- BTC pts in our cohort. These findings warrant further prospective validation.Ethics Approval This study was conducted in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki declaration and its later amendments. Ethics approval was obtained from the Institutional Review Boards (IRBs) of all participating centers. As this was a retrospective study involving de-identified data, the requirement for informed consent was waived by the respective IRBs.