Background: aHCC patients (pts) with Vp3-4 PVTT have a poor prognosis. HAIC combined with immune checkpoint inhibitors and targeted therapies has shown local control and survival benefits in aHCC. However, the optimal combination in aHCC pts with Vp3-4 PVTT remains unclear. Here, we reported the preliminary efficacy and safety of HAIC combined with tislelizumab and lenvatinib in this population. Methods: In this ongoing, single-site, prospective, single-arm, phase II study, eligible pts were aged ≥18 years, histologically confirmed aHCC, ECOG PS ≤1, Child-Pugh A/B, and had at least 1 measurable lesion per RECIST 1.1. Pts received HAIC with modified FOLFOX (oxaliplatin, 85 mg/m², leucovorin 400 mg/m², 5-fluorouracil bolus 400 mg/m² on day 1; and 5-fluorouracil infusion 2400 mg/m² for 46 h), combined with lenvatinib (8 or 12 mg QD for body weight <60 or ≥60 kg) and tislelizumab (200mg Q3W). HAIC was conducted repeatedly on demand. The primary endpoint was the objective response rate (ORR) per RECIST 1.1. Secondary endpoints included the ORR per mRECIST, disease control rate (DCR), surgical conversion rate, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: From June 2021 to January 2023, 27 aHCC pts with Vp3-4 PVTT were enrolled; of these, 22 pts were valuable for efficacy and safety analyses. The 22 pts were characterized with a median age of 52.5 years (range 33-72), 40.9% ECOG PS 0, 90.9%Child-Pugh A, and 45.5% extrahepatic metastasis. Till data cut-off (January 20, 2023), median follow-up was 11.3 months (95% CI, 6.0-13.1), 17 pts were alive and 14 pts remained on treatment. The ORR was 45.5% (95% CI, 25.1%-67.3%) with all partial responses per RECIST 1.1. Notably, 17 of 22 pts (77.3%; 95% CI, 54.2%-91.3%) achieved objective response as per mRECIST, with 6 (27.3%) complete responses and 11 (50%) partial responses. The DCR was 90.9% (95% CI, 69.4%-98.4%) either by RECIST 1.1 or mRECIST. Surgical conversion was achieved in 22.7% (5/22; 95% CI, 8.7%-45.8%) pts. Median PFS was not reached, with a 6- and 12-month PFS rate of 50% and 27.3%. OS data was not mature by the cut-off date. TRAEs were reported in 18 of 22 pts (81.8%). Most common TRAEs of any grade were hypertension (11/22, 50%), neutropenia (10/22, 45.5%), and aspartate aminotransferase (AST) increased (7/22, 31.8%). Grades ≥3 TRAEs occurred in 6 pts (27.3%), including 3 neutropenia (13.6%), 2 abdominal pain (9.1%), and 1 AST increased (4.6%). Conclusions: HAIC combined with tislelizumab and lenvatinib showed encouraging clinical activity and acceptable toxicity in aHCC pts with Vp3-4 PVTT, suggesting that this combination could be considered in this population. Study enrollment is ongoing, more mature data will be presented later. Clinical trial information: ChiCTR2200064384.