Background: Tyrosine kinase inhibitor combined with immune checkpoint inhibitor has been reported a synergetic survival benefit in patients with unresectable hepatocellular carcinoma (uHCC). TACE induces tumor necrosis and tumor antigen release was believed to increase immune responses of anticancer immunotherapies. This study aimed to evaluate the safety and efficacy of fruquintinib combined with sintilimab plus TACE for uHCC. Methods: This study was a single-arm, open-label phase Ⅱ exploratory clinical study (NCT05971199). Eligible patients were China liver cancer stage (CNLC) Ⅱb-Ⅲa and not candidates for surgical resection or ablation, or liver transplantation, at least one target lesion evaluable, ECOG performance status of 0-1, and Child-Pugh score ≤7. Enrolled patients would receive treatment with TACE (TACE was repeated on demand, but < 5 times) followed by sintilimab 200 mg every 3 weeks and fruquintinib (5 mg QD, 2w on/1w off) until intolerable toxicity or disease progression. The primary endpoint was progression free survival (PFS). The secondary endpoints included adverse events (AEs), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) per mRECIST. Results: As of August 20, 2023, 15 enrolled patients with uHCC were treated. Mean follow-up time is 10.7 months. The median age was 58 years. At present, 10 patients were included for efficacy and safety analysis evaluation. Number of patients with CNLC stage Ⅱb and Ⅲa was 0 (0 %) and 15 (100 %), respectively. The median PFS and OS data are not yet mature. The ORR and DCR were 80% and 100% respectively based on mRECIST (1 CR, 10%; 7 PR, 70%; 2 SD, 20%). The most common (≥ 10%) TRAEs (≥ Grade 3) were elevated glutamic oxaloacetic transaminase, hypertension, proteinuria. No unexpected toxicity or treatment-related deaths occurred. Conclusions: Fruquintinib combined with sintilimab and TACE is a promising and tolerable therapeutic regimen for patients with CNLC Ⅱb-Ⅲa uHCC. This study is still ongoing and further follow-up is required to obtain final survival results. Clinical trial information: NCT05971199.