Background <p>Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have poor overall survival (OS). Hepatic arterial infusion chemotherapy (HAIC) and transarterial chemoembolization (TACE), including conventional TACE (c-TACE) and drug-eluting bead TACE (DEB-TACE), are widely used to treat ICC, but the efficacy of these therapies has not been fully demonstrated. This study aimed to compare the efficacy of HAIC and TACE in unresectable ICC patients.</p> Methods <p>This retrospective cohort study included unresectable ICC patients who received HAIC, c-TACE or DEB-TACE as initial treatment between June 2016 and October 2023 at three hospitals. The median OS (mOS), tumor response, and incidence of adverse events (AEs) were compared and propensity score matching (PSM) was used to reduce selection bias.</p> Results <p>A total of 181 patients with unresectable ICC received HAIC (<i>n</i> = 24), c-TACE (<i>n</i> = 73) and DEB-TACE (<i>n</i> = 84). The HAIC group had significantly higher mOS (10.3 vs. 5.1 months, <i>p</i> = 0.0042), objective response rate (ORR) (29.2% vs. 4.1%, <i>p</i> = 0.002) and disease control rate (DCR) (95.8% vs. 43.8%, <i>p</i> &lt; 0.001) than the c-TACE group. There was no significant difference between the HAIC and DEB-TACE groups in improving mOS (10.3 vs. 12.5 months, <i>p</i> = 0.61). Results remained consistent after PSM. The c-TACE and DEB-TACE groups had a higher incidence of AEs compared with the HAIC group. After matching, there was no significant difference in the incidence of AEs between groups.</p> Conclusion <p>HAIC improves ICC patient prognosis better than c-TACE. Both HAIC and DEB-TACE are superior treatment options for unresectable ICC.</p> Key Points <p><Emphasis Type="BoldItalic">Question</Emphasis> <i>The evidence of comparative effectiveness between hepatic arterial infusion chemotherapy (HAIC) and transarterial chemoembolization (TACE) is insufficient.</i></p> <p><Emphasis Type="BoldItalic">Findings</Emphasis> <i>HAIC significantly improved median overall survival, tumor response, and prognosis while reducing adverse events compared to convention TACE (c-TACE) in unresectable intrahepatic cholangiocarcinoma (ICC) patients.</i></p> <p><Emphasis Type="BoldItalic">Clinical relevance</Emphasis> <i>HAIC significantly improves OS and tumor response in patients with unresectable ICC compared to c-TACE, but HAIC shows no significant difference from drug-eluting bead-TACE. Notably, HAIC shows no significant difference in adverse events compared to both c-TACE and DEB-TACE.</i></p> Graphical Abstract <p></p>