Background: Hepatocellular carcinoma (HCC) patients (pts) with macrovascular invasion (MVI) have dismal prognosis, and limited evidence for perioperative therapies is available. This study aims to explore the safety and feasibility of perioperative tislelizumab (a PD-1 monoclonal antibody) plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Methods: This single-arm phase II trial enrolled resectable HCC pts with MVI, as assessed by the investigators before surgery. Pts were treatment-naïve, with ECOG of 0-1, and had adequate organ and bone marrow function. Eligible pts received 3 cycles of tislelizumab (200mg, d1, Q3W) and concurrent IMRT (45 Gray in 15 fractions). After surgical feasibility assessment, HCC resection is scheduled after IMRT, followed by adjuvant tislelizumab up to one year. The primary endpoints include overall response rate (ORR) and overall survival (OS). Secondary endpoints are significant pathological response (viable tumor cells <10%), recurrence-free survival (RFS) and safety. Results: From Oct 21, 2020 to Feb 15, 2023, 30 pts were enrolled, with most pts 26 (86.7%) were males and 29 pts (96.7%) had HBV infection. 28 pts (93.3%) had Child-Pugh grade A and 29 pts (96.7%) had ECOG PS 0. The types of vascular invasion were main portal vein (n=9), branched portal vein (n=15), major hepatic vein (n=2), or both portal and hepatic vein (n=4). In 30 pts, ORR was 30.0% (RECIST1.1), DCR was 36.6% and the median OS was 18.7 months. 15 (50%) underwent radical surgical resection followed by adjuvant tislelizumab, 10 (66.7%) achieved a significant pathological response. By Sep 30, 2023, median RFS was not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. Of the pts who underwent surgery, 7 (46.7%) pts experienced tumor relapse with 1-year RFS rate was 60%. The most common events of any grade were increased thyroid stimulating hormone (TSH) (83.3%), leukopenia (60.0%) and anemia (53.3%). 4 (13.3%) pts experienced grade 3 TRAEs (leukopenia, increased TSH and increased alkaline phosphatase).An exploratory analysis suggests that pts who underwent surgery have longer median OS (not reached versus 7.0 months, p=0.025). AFP reduction after perioperative therapy was found to be prognostic of RFS. Conclusions: The effectiveness and tolerability of tislelizumab plus radiotherapy as perioperative therapy for resectable HCC with MVI is worth further exploration. Clinical trial information: ChiCTR2000036385.