Background: Combination treatment with an immune checkpoint inhibitor and an anti-VEGF antibody is recommended as the standard care for advanced hepatocellular carcinoma (HCC). However, the efficacy of systemic therapy is less than satisfactory in BCLC stage C. Transarterial chemoembolization (TACE) combined with systemic therapy may synergistically improve patients’ clinical outcomes and obtain survival benefits. Intra-arterial infusion of Sintilimab and Bevacizumab has not been assessed previously. This study aimed to evaluate the safety and efficacy of TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab in patients with BCLC stage C HCC. Methods: This prospective, single-arm phase II study recruited 16 patients with advanced HCC. Main inclusion criteria: aged ≥ 18 years; a confirmed HCC (BCLC stage C) based on the ALSLD with either pathological or imaging findings; no previous systemic/locoregional anticancer treatment; Child-Pugh score ≤7; ECOG performance status: 0-1. Patients were treated with TACE (30-40mg of pirarubicin, 30-40mg of lobaplatin, and lipiodol) plus Sintilimab (200mg, intra-arterial infusion, d1, Q3W) and Bevacizumab (7.5mg/kg, intra-arterial infusion, d1, Q3W) for four cycles, followed by maintenance therapy with Sintilimab (200mg, intravenously, d1, Q3W) and Bevacizumab (15mg/kg, intravenously, d1, Q3W) to a maximum total cycle of eighteen unless any evidence of disease progression or unacceptable side effects. The primary endpoint was objective response rate (ORR) (assessed with mRECIST v1.1) and the secondary endpoints included disease control rate (DCR), time to progress (TTP), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Drug safety was investigated according to CTCAE (version 5.0). Results: From September 2021 to December 2022, 16 patients with a median age of 52 years (range:38 -73) were enrolled. 12 (75%) patients with HBV infection and 6 (38%) with extrahepatic metastasis. 14 (88%) patients were classified as Child-Pugh A class. With a median follow-up of 5.4 months (range 3.9-14.3), the ORR was 63% (95%CI, 36.4%- 84.8%) with 3 CR and 7 PR per mRECIST v1.1, and the DCR was 69% (95%CI, 41.3%-89.0%). The median PFS was not reached. Adverse events in 31% of 16 patients were hypertension (3, 19%), fatigue (1, 6%), and proteinuria (1, 6%). The most common adverse event of grade 3 was hypertension (2, 13%). There were no treatment-related serious adverse events. Conclusions: TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab as the first-line strategy for advanced HCC patients (BCLC stage C) demonstrated a promising value by improving ORR, with acceptable side effects. Clinical trial information: NCT04796025.