Background: Most patients with hepatocellular carcinomas (HCC) are diagnosed at intermediate to advanced stages, at which they have missed the opportunity for curative resection. Combination therapy with tyrosine kinase inhibitors, anti-PD-1 antibodies and HAIC has achieved a high response rate for advanced HCC. Phase 3 study also showed the survival benefit of donafenib for unresectable HCC compared with sorafenib. This study aimed to explore the efficacy and safety of conversion therapy with HAIC plus donafenib, anti-PD-1 antibodies in the patients with initially unresectable HCC. Methods: This was a prospective single-arm, phase 2 study (ChiCTR2200059297). Eligible patients were adults who were newly diagnosed with HCC, not amenable to curative resection, with an ECOG PS 0-1 and Child-Pugh class A/B7. Patients received FOLFOX HAIC (oxaliplatin 85 mg/m² 3h, leucovorin 200 mg/m² 2h, fluorouracil bolus 400 mg/m² in the first 15 minutes, and fluorouracil infusion 2400 mg/m² for 46 hours) Q3W plus donafenib 200mg bid, anti-PD-1 antibodies Q3W until disease progression or unacceptable toxicity, followed by multidisciplinary assessment and potential hepatectomy. The primary endpoint was conversion success rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), pathologic complete remission (pCR), event free survival (EFS), overall survival (OS) and safety. Results: From Sep 2021 to Dec 2022, 22 pts were enrolled with a median age of 57 years (range, 43-76). The study population was predominantly HBV-positive (71.4%). All pts were in BCLC stage C, the rate of macro vascular invasion and retroperitoneal lymph node metastasis were 71.4% and 28.6% respectively. As of Jan 31, 2023 cut-off, 19 pts were evaluable for response. The conversion success rate was 52.6% (10/19) and 4 pts received hepatectomy. Among the 4 pts, 1 (25%) case achieved complete pathological response and 2 (50%) cases achieved major pathological response. Based on mRECIST, ORR was 84.2% (95%CI, 0.60-0.90) with 2 (10.5%) complete responses (CR) and 14 (73.7%) partial responses (PR). DCR was 94.7% (95%CI, 0.74-0.99). The 12 months’ EFS rate was 50.4%, the median EFS and OS were not reached. All pts were evaluable for toxicity, and 18 (81.8%) pts had at least one treatment-emergent AE (TEAE). TEAEs occurring in ≥20% of pts were decreased platelet count (36.4%), hand-foot skin reactions (31.82%), rash (27.3%), elevated ALT (22.7%) and decreased WBC count (22.7%). 10 (45.5%) pts had level 3 TEAE. There were no level 4 and 5 TEAEs. Conclusions: A triple combination of donafenib, anti-PD-1 antibodies and HAIC is well tolerated and effective, it’s a feasible conversion therapy for patients with unresectable locally intermediate to advanced HCC. The enrollment and follow-up are continuing. Clinical trial information: ChiCTR2200059297.