Background: Sintilimab plus IBI305, a bevacizumab biosimilar, showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for patients with unresectable hepatocellular carcinoma. Hepatic arterial infusion chemotherapy is an intraarterial procedure that has been widely used in Asia, with high response rate. This trial was designed to assess the feasibility and efficacy of HAIC combined with sintilimab and IBI305 in advanced unresectable hepatocellular carcinoma. Methods: This is a prospective, single-arm phase II study. Patients with histologically or cytologically diagnosed or clinically confirmed hepatocellular carcinoma, China liver cancer staging (CNLC) stage IIb-IIIb, no previous systemic treatment, Child-Pugh classification A or B, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. Patients received FOLOFOX-HAIC, followed by intravenous sintilimab (200 mg every 3 weeks, four cycles) and intravenous IBI305 (7.5 mg/kg every 3 weeks, three cycles). The primary endpoint was objective response rate (ORR) per mRECIST. Secondary endpoint were surgical conversion rate, pCR rate and R0 resection rate. The study is registered with Clinicaltrials.gov: NCT05029973. Results: Between May, 2021 to Sep, 2021, a total of 30 eligible patients were enrolled: median age 54.5 years (range 37-73); M:F 27:3; CNLC stage IIb/IIIa/IIIb: 3/16/11; Child-Pugh class A/B: 28/2; ECOG PS 0/1: 26/4. There were 23(76.7%) patients with hepatitis B and 5(16.7%) with hepatitis C. The median tumor size was 8.75 cm (interquartile range [IQR], 4.9-10.5), 60.0% pts present vascular invasion, and 36.7% had extrahepatic metastasis. Of 30 pts evaluable for response, 20 (66.7%; 95% CI: 47.2%-82.7%) achieved confirmed partial response, and became eligible for surgical resection. Finally, 14 of them received surgical resection and all (100%) achieved R0 resection, 3 pts completed radiofrequency ablation (RAF), 3 pts refused resection or RFA. The pCR rate in the patients completed pathological examination was 52.6% (95% CI: 28.9%-75.6%). The most common TRAEs included hypertension (23.3%), rash (16.7%), and abnormal liver function (10.0%). No grade 3-4 TRAEs were observed. Of note, in patients received surgery, 1 developed grade 1 biliary fistula, 1 developed hepatic failure and finally lead to death Conclusions: HAIC Combined With sintilimab and IBI305 resulted in a promising ORR, R0 surgical conversion rate and pCR rate with a manageable safety for initial unresectable advanced hepatocellular carcinoma. Further follow-up is ongoing. Clinical trial information: NCT05029973.