Objective: To explore the safety and efficacy of postoperative adjuvant targeted therapy combined with immunotherapy in patients with biliary tract carcinoma (BTC) with high-risk factors for recurrence. Methods: A retrospective analysis was performed on the clinical data of 24 patients with BTC complicated with high-risk factors for recurrence, who underwent surgical resection in our hospital from January 2023 to December 2023, declined adjuvant chemotherapy, and voluntarily opted for targeted therapy combined with immunotherapy. The clinicopathological characteristics, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs) of the enrolled patients were recorded. Survival analysis was performed using the Kaplan-Meier method, and the Cox proportional hazards regression model was used to analyze the factors affecting RFS. Results: During the follow-up of the 24 patients, 12 patients (50.00%) developed recurrence and 7 patients (29.17%) died. The median RFS was 12 months, and the median OS was not reached. Among them, the median RFS and median OS were not reached in patients with R0 resection and high-risk factors for recurrence, while the median RFS was 8 months and the median OS was not reached in patients with R1 resection. The RFS rate and OS rate of patients with R0 resection and high-risk factors for recurrence were significantly higher than those of patients with R1 resection. Exploratory prognostic factor analysis showed that age <60 years, single tumor, R0 resection, no lymph node metastasis, no vascular invasion, and single high-risk recurrence factor were prognosis factors affecting RFS (all P < 0.05). In terms of safety, the incidence of all-grade AEs was 79.17% (19/24), and the incidence of grade 3 AEs was 8.33% (2/24). No treatment-related death occurred. Conclusion: Postoperative adjuvant targeted therapy combined with immunotherapy shows certain efficacy and controllable safety in BTC patients with high-risk factors for recurrence. Age <60 years, single tumor, R0 resection, no lymph node metastasis, no vascular invasion, and single high-risk recurrence factor are prognosis factors affecting RFS in this research.