BACKGROUND: The prognosis of biliary tract cancer (BTC) is poor, and recurrence rates remain high even after curative resection. This study aimed to compare the efficacy and safety of capecitabine and 5-fluorouracil/leucovorin (FL) as adjuvant treatments following curative resection in patients with BTC. METHODS: We retrospectively reviewed the medical records of patients with BTC (including gallbladder and extrahepatic and intrahepatic bile duct cancers) who underwent curative surgical resection and adjuvant chemotherapy between 2011 and 2023. The recurrence-free survival, overall survival, and adverse events were investigated between the two groups. RESULTS: Of the 263 patients, 85 and 178 received capecitabine and FL, respectively. The recurrence-free survival and overall survival did not show statistically significant differences between the capecitabine and FL groups. After propensity score matching, the capecitabine group showed significantly longer overall survival (median, NA [52 - NA] vs. 43 months [32 - NA], p = 0.032). Although severe adverse events did not differ between both groups (29.4% vs. 20.2%, p = 0.135), overall adverse events, including anemia, thrombocytopenia, hand-foot syndrome, and skin color change, were significantly more frequent in the capecitabine group (90.6% vs. 57.9%, p < 0.001). After propensity score matching, severe adverse events (30.3% vs. 14.5%, p = 0.032) and overall adverse events (90.8% vs. 65.8%, p < 0.001) were significantly more frequent in the capecitabine group. CONCLUSION: In patients with curatively resected BTC, capecitabine demonstrated superior efficacy in prolonging overall survival, whereas FL had a more favorable safety profile with fewer adverse events.