Objective To compare hepatic artery infusion chemotherapy (HAIC) with transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma combined with both anti-angiogenesis and immunotherapy for effectiveness and safety. Methods Ninety-three patients with hepatocellular carcinoma including stage B 18 cases and stage C 75 cases, and 74 males, 19 females with a median age of 57 (27-78) in Tianjin Medical University Cancer Hospital from January 2019 to December 2020 were studied retrospectively. In the treatment combined with anti-angiogenesis and immunotherapy, 50 cases received TACE and 43 cases received HAIC. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 was used to evaluate the efficacy of treatment. The primary endpoints were both objective response rate (ORR) and disease control rate (DCR), and the secondary endpoints both median progression free survival (mPFS) and median overall survival (mOS). Results Both ORR (72.09% vs. 44.00%, P=0.006) and DCR (88.37% vs. 60.00%, P=0.002) were significantly more in HAIC group than in TACE group. The median follow-up duration was 12.13 months in HAIC group and 11.95 months in TACE group. mPFS in TACE group was 11.83 months (95%CI: 4.36-19.31 months) with mOS 17.93 months (95%CI: 11.80-24.06 months). Both mPFS and mOS did not reach in HAIC group. There were significant differences in PFS and OS between two groups (P=0.017; P=0.007). Conclusions The patients with advanced hepatocellular carcinoma would benefit from HAIC combined with both anti-angiogenesis and immunotherapy in disease control and survival with less side effects and better safety when compared with TACE combination treatment.