e16178 Background: In Phase III study (ZGDH3), donafenib showed the survival benefit and better safety compared with sorafenib as the first-line treatment for uHCC. Recently, combination therapies have shown favorable results in patients with HCC. Some studies have shown that molecular targeted drugs combined with anti-PD1 antibodies and TACE exhibit improved anti-tumor efficacy compared with monotherapy. This study aimed to evaluate the efficacy and safety of the combination therapy of donafenib,anti-PD-1 antibodies and TACE as first-line treatments for HCC patients in the real world. Methods: This single-center retrospective study involved patients with histopathologically/cytologically or clinically confirmed HCC at Zhejiang Cancer Hospital between July 2021 and June 2023. Eligible patients were treated with donafenib (100 mg po bid) combined with TACE and anti-PD-1 antibodies until the point of disease progression, death, or intolerable toxicity. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) datas of patients were collected and analyzed according to the mRECIST, and the incidence of adverse events (AEs) was evaluated using CTCAE 5.0. Results: There were 34 patients in this study (Table). The median age was 64 years (IQR: 57, 69) at the data cut-off in January 2024, with 94.1% of the population being male and 82.4% having HBV infection. Of these patients, 5(14.7%) were classed as BCLC stage A, 11(32.3%) were classed as BCLC stage B, and 18 (52.9%) were BCLC stage C. The median PFS was 7.9 months (95%CI, 5.6–NA), and median OS was not reached, respectively, the 12-month PFS and OS rates were 46.9% (95%CI: 16.8%-72.5%) and 96.9% (95%CI: 79.8%-99.6%). The ORR and DCR for all patients were 73.5% and 97.1%, respectively, based on both mRECIST (CR 3 [8.8%], PR 22 [64.7%], SD 8 [23.5%]). The surgical conversion rate was 26.5%. Treatment-related adverse events (TRAE) of any grade were observed by 18 patients (52.9%), of which 4 patients (11.8%) had grade 3 TRAE. No grade 4 or 5 TRAE was observed. Conclusions: The study indicated that donafenib combined with TACE and anti PD-1 antibodies exhibited encouraging efficacy and favorable safety profile in patients with HCC. [Table: see text]