BACKGROUND: Bile duct carcinoma (BTC) is an uncommon malignant tumor of the gastrointestinal tract. Management is limited after the progress of first-line treatment. Immune checkpoint inhibitors (ICIs) have been proven popular in solid tumors. Immunotherapy plus chemotherapy has been a standard scheme in the management of multiple types of cancer. However, their efficacy and safety still need further exploration in patients who diagnosed BTC. This research mainly discusses the efficacy of immunotherapy in the second-line use of cholangiocarcinoma. METHODS: In total, 126 individuals with BTC diagnosis from 2014 to 2024, who were treated with first-line or neoadjuvant treatment but were evaluated for progression or intolerance, were retrospectively included. All patients received standard chemotherapy, 57 received ICIs in combination with targeted therapy or not, and 69 did not. Patients were divided into simple chemotherapy (SC) and CT. Differences in efficacy, adverse events, progression-free survival (PFS), overall survival (OS), progressive disease (PD), and efficacy of multiple factors and efficacy were analyzed. The primary endpoint is defined as OS. The secondary endpoint is defined as PFS, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse reactions (TRAEs). RESULTS: The PFS and OS of 4.68 and 30.26 months for ICIs with or without targeted therapy were proven statistically significant ( CONCLUSION: Our work concluded that immunocombined chemotherapy with or without specific treatment showed significant antitumor activity and acceptable safety. Immune checkpoint inhibitors are likely to be a reliable second-line therapy for advanced BTC.