Background: Unresectable hepatocellular carcinoma (uHCC) patients (pts) had high unmet medical needs in practice. Retrospective studies suggested a potent antitumor effect and long-term survival benefit of hepatic arterial infusion chemotherapy (HAIC) plus programmed death-1 inhibitor and lenvatinib. This prospective phase II study aimed to evaluate the efficacy and safety of HAIC combined with lenvatinib and tislelizumab in uHCC pts. Methods: Eligible pts were aged ≥18 years and had histologically confirmed uHCC, ECOG PS ≤1, Child-Pugh (C-P) A/B, and ≥1 measurable lesion per RECIST 1.1. Pts received HAIC of modified FOLFOX (oxaliplatin, 85 mg/m²; leucovorin, 400 mg/m²; 5-fluorouracil bolus, 400 mg/m² on day 1; 5-fluorouracil infusion, 2400 mg/m² for 46 h), lenvatinib (8 or 12 mg once daily for body weight <60 or ≥60 kg), and tislelizumab (200 mg every 3 weeks). HAIC was allowed to repeat on demands. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included ORR per mRECIST, disease control rate (DCR), surgical conversion rate, progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Between June 2021 and January 2023, 46 pts were enrolled. The median age of pts was 51-year-old, most were male 42 (91.3%), ECOG PS 0 33 (71.7%), C-P A 44 (95.7%), tumor diameter ≥10 cm 31 (67.4%), multiple tumors 33 (71.7%), vascular invasion 38 (82.6%), extrahepatic metastasis 7 (15.2%). As of August 15, 2023, . All pts entered efficacy and safety analysis, ORR was 52.2% (0 complete response [CR], 24 partial response [PR]) per RECIST 1.1; ORR was 84.8% per mRECIST, with 5 CR and 34 PR. DCR was 95.6% per either RECIST 1.1 or mRECIST. Surgical conversion rate was 21.7% (10/46). Median PFS was 10.9 (95% CI, 8.0-13.8) months; 12-month OS rate was 41.3%. COX analysis revealed that ECOG PS 1 (HR, 3.17; 95% CI, 1.43-7.03; p=0.005), multiple tumors (HR, 3.68; 95% CI, 1.22-11.14; p=0.021), and extrahepatic metastasis (HR, 4.04; 95% CI, 1.57-10.40; p=0.004) were independently associated with poor PFS. Any-grade AEs occurred in 43 (93.5%) pts, the most common were proteinuria (43.4%), aspartate aminotransferase (AST) increased (35.8%), and alanine aminotransferase (ALT) increased (32.1%). Grades ≥3 AEs occurred in 10 (21.7%) pts and mainly included AST increased (7.5%), hypertension (3.8%), and hyperbilirubinemia (3.8%). Conclusions: HAIC combined with lenvatinib and tislelizumab showed meaningful clinical benefits and acceptable safety in uHCC pts. The study is ongoing, OS will be reported later. Clinical trial information: ChiCTR2200064384.