Background: Chemoembolization plus hepatic arterial infusion chemotherapy significantly improved ORR and PFS over chemoembolization alone in patients with uHCC in previous study. And donafenib showed the survival benefit and better safety compared with sorafenib in a Phase III trial. In consideration of synergism, we evaluated the safety and efficacy of TACE plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody in patients with uHCC. Methods: We retrospectively analyzed the patients who were diagnosed as unresectable hepatocellular carcinoma and received the treatment of TACE plus HAIC combined with donafenib, anti-PD-1 antibody as first-line therapy from Nov 2021 to Nov 2022 in Harbin Medical University Cancer Hospital. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progress free survival (PFS), overall survival (OS), time to response (TTR) and safety. Results: Of 36 patients included in the analysis, all of them received first-line treatment of TACE (embolization of pirarubicin hydrochloride 40mg, iodized oil 10-20ml with or without gelatin sponge) plus HAIC (oxaliplatin 85 mg/m² 2h, leucovorin 400 mg/m² 1h, fluorouracil bolus 400 mg/m² in the first 10 minutes, and fluorouracil infusion 2400 mg/m² for 46h) combined with donafenib 200mg bid, anti-PD-1 antibody Q3W. The median age was 58 years (range, 44-80). The study population was predominantly male (75%), and 89% were HBV-positive. Patients were classified as BCLC stage A (8.3%), stage B (8.3%) and stage C (83.4%). The rates of patients with portal vein tumor thrombus and extrahepatic metastasis were 69% and 11% respectively. 30.6% patients received interventional therapy before the combination treatment. By Feb 2023, 23 patients had received at least one imaging evaluation, 19(82.6%) of them achieved partial response, ORR and DCR were 82.6% and 100% per modified RECIST criteria respectively. And the median TTR was 1.1 months. With 3.8 months of median follow-up time, the 6-month PFS rate was 51.2%. The median PFS and OS were not reached. All 36 patients had at least one treatment-related AE (TRAE), and treatment-related deaths did not occur in this study. Grade 3 TRAEs occurred in 8 (22.2%) patients, and no grades 4 or 5 were reported. The most common TRAEs included alanine aminotransferase increased (77.8%), alkaline phosphatase increased (77.8%), platelet count decreased (69.4%) and blood bilirubin increased (63.9%). Conclusions: Chemoembolization plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody are effective and tolerable for uHCC patients.