BACKGROUND: Previous research has shown that combining tyrosine kinase inhibitors (TKIs) with immunotherapy results in synergistic clinical efficacy. Cadonilimab, the first approved bi-specific antibody targeting PD-1 and CTLA-4, was studied to evaluate its efficacy and safety in combination with Lenvatinib as a first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). METHODS: A retrospective study was conducted on 29 uHCC patients diagnosed at Nanfang Hospital, Southern Medical University, between July 7, 2022, and March 3, 2023. Patients received Cadonilimab (10 mg/kg, IV, every 3 weeks) combined with Lenvatinib (8 mg, orally, daily). The primary endpoint was the objective response rate (ORR), with secondary endpoints including disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), median time to progression (mTTP), and safety. RESULTS: By April 2023, 29 patients had been enrolled in the study. The ORR was 37.9 %, DCR was 82.8 %, mPFS was 8.1 months, mTTP was 8.2 months, and mOS was not reached. A total of 93.1 % of patients experienced at least one treatment-related adverse event (TRAE). The most common adverse events were weight loss (51.7 %), increased aspartate aminotransferase (48.3 %), leukocytopenia (48.3 %), and neutropenia (48.3 %). TRAEs of grade 3 or higher occurred in 51.7 % of patients, with no grade 4 TRAEs observed. CONCLUSION: This study demonstrated the efficacy and safety of this combination, potentially improving outcomes as a first-line therapy, and offering a novel therapeutic approach for advanced HCC.