Background: Immune-checkpoint inhibitors, in combination with targeted therapy and local therapy, have been developed as promising treatment for unresectable hepatocellular carcinoma (uHCC) of intermediate stage. This study aimed to assess the efficacy and safety of cadonilimab(a tetravalent PD-1/CTLA-4 bispecific antibody) plus Lenvatinib (Len) and transarterial chemoembolization (TACE) in the treatment of intermediate HCC. Methods: This open label, multicenter phase II trial enrolled patients with histologically or clinically confirmed intermediate uHCC to receive TACE followed by cadonilimab 10mg/kg every 3 weeks plus Len until disease progression or intolerable toxicity. The primary endpoint was progression free disease (PFS) according to RECIST v1.1. The secondary endpoint includes safety, overall survival (OS), PFS according to modified RECIST (mRECIST), and objective response rate (ORR), disease control rate (DCR) and duration of response (DoR) by both RECIST v1.1 and mRECIST. Results: From June 2022 to May 2023, 78 patients were screened and 60 patients enrolled. As of August 15, 2023, 60 patients received at least once cadonilimab and the median duration of follow-up was 5.1 months. The average number of TACE procedures per patient was 1.70. The median PFS and OS were not reached, while the 6-month PFS rate was 77.1% (95% CI, 60.8-87.3) per RECIST v1.1 and 75.6% (95% CI, 59.5-86.0) per mRECIST. The ORR and DCR were 35.0% (95% CI, 23.1-48.4) and 96.7% (95% CI, 88.5-99.6) according to RECIST v1.1 and 85.0% (95% CI, 73.4-92.9) and 95.0% (95% CI, 86.1-99.0) according to mRECIST. 9 patients (15.0%) achieved complete response per mRECIST. The incidence of grade≥3 treatment-related adverse events (TRAEs) was 68.9%. The incidence of grade≥3 adverse events related to cadonilimab was 45.9%.The most common TRAEs included thrombocytopenia, aspartate aminotransferase increased, and alanine aminotransferase increased. Conclusions: Combination of TACE and cadonilimab plus len showed promising efficacy and manageable toxicity in intermediate uHCC. Benefit of control on tumor progression after TACE and lasting survival can be expected. Clinical trial information: NCT05319431.