Background: The combination of anti-angiogenesis and immune checkpoint inhibitors has been proved to improve clinical outcomes of uHCC, but efficacy still does not meet clinical needs. In Phase III study (ZGDH3), donafenib showed the survival benefit and better safety compared with sorafenib. HAIC significantly improved treatment responses over TACE in patients with large uHCC in a Phase III trial. Considering the different mechanisms, this study aimed to investigate the safety and efficacy of HAIC combined with donafenib and sintilimab in patients with uHCC. Methods: This is a prospective, single-arm phase II study (NCT05166772). Patients with histologically diagnosed uHCC, no previous systemic treatment, Child-Pugh A5-B7, ECOG performance status (PS) of 0 or 1 were eligible for inclusion. Enrolled patients received donafenib (200 mg, bid), sintilimab (200 mg, q3w) and HAIC (oxaliplatin 85 mg/m²2h, leucovorin 400 mg/m²2h, fluorouracil bolus 400 mg/m² in the first 10 minutes, and fluorouracil infusion 1200 mg/m² for 23 hours, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Results: From December 2021 to December 2022, 24 patients (19 men and 5 women; median age, 58 years) were enrolled: BCLC stage A/B/C: 2/9/13; Child-Pugh class A/B: 23/1; ECOG PS 0/1: 23/1. There were 19 (79.2%) pts with hepatitis B. The median tumor size was 7.9 cm (range, 1.7-16.3), 45.8% pts presented macro vascular invasion, the invasion rates of Vp3, Vp4 and inferior vena cava were 25.0%, 4.2% and 8.3% respectively, 16.7% had extrahepatic metastasis. As of February 10, 2023, the median follow-up time was 107 days, the median number of HAIC was 3 times (range, 1-8). Based on mRECIST, the ORR was 78.3% (95% CI, 56.3%-92.5%) with 3 (13.0%) complete responses (CR) and 15 (65.2%) partial responses (PR). The disease control rate (DCR) was 95.7% (95% CI, 78.1%-99.9%). Of 23 pts evaluable for response, the conversion success rate was 65.2% (15/23), 10 of them (43.5%) received hepatectomy, 3 cases (30.0%) achieved complete pathological response and 5 cases (50.0%) achieved major pathological response. The median time to response (TTR) was 1.9 months (range, 1.2-5.2). The median progression-free survival (PFS) was 10.2 months (95% CI, NR) and 6 months PFS rate was 89.1%. The median duration of response (DoR) was not reached. Any grade treatment-emergent adverse events (TEAEs) occurred in 95.8% of pts. The most common TEAEs were thrombocytopenia (66.7%), neutropenia (45.8%), rash (41.7%). Grade 3-4 TEAEs occurred in 37.5% of pts. No grade 5 TEAEs were observed. Conclusions: Preliminary analysis showed that donafenib combined with HAIC and sintilimab showed promising clinical benefits and acceptable toxic effects in patients with uHCC. The enrollment and follow-up are continuing. Clinical trial information: NCT05166772.