Background: Macrovascular tumor invasion in the portal vein system is associated with poor survival and response to therapy. The Japanese portal vein invasion (Vp) classification is based on anatomical location of the thrombus and has been reported to predict prognosis in Asian cohorts of patients. Systemic treatment (ST) options have been increasing over the last decade, coupled with a refinement of radiation (RT) delivery and surgical techniques. Modern literature about HCC and PVTT is scarce in the West. Aim of this study was to characterize outcomes of PVTT patients stratified by Vp categories and by treatment strategies in a Western cohort of HCC patients. Methods: A total of 837 patients with HCC, treated at our tertiary referral center between 2010 and 2022, were retrospectively reviewed. 136 (16.3%) patients with PVTT at the time of diagnosis were identified. PVTT was diagnosed by contrast-enhanced computed tomography or magnetic resonance imaging. The extent of portal tumor-in-vein burden was characterized according to the Liver Cancer Study Group of Japan classification. Treatment modalities were delineated. Median OS was calculated for each group. Cox proportional hazard was used to compare OS between groups. Results: Etiology of liver disease was chronic hepatitis B in 18 (13%) patients, chronic hepatitis C in 79 (57%), alcohol in 53 (39%) and NASH in 10 (7%). Our group comprised 8 Vp1, 16 Vp2, 53 Vp3 and 59 Vp4 patients. 42% were in class Child-Pugh A, 42% B and 16% C. 14 (10%) patients underwent surgical resection of their tumor, 31 (23%) received radiation therapy, 90 (68%) were treated with systemic therapy, while 27 (23%) only received best supportive care (BSC). Median OS was 7.2 months in all comers; 16.0, 3.6, and 1.9 months when stratified by Child-Pugh class A, B, C respectively. Patients lived longer when they had more limited PVTT extent (Table). There was a trend towards worse OS in patients with Vp4 tumors compared to more peripheral thrombi (median OS 4.7 vs 12.8 mo, p=0.055). Patients treated with both ST and RT had a better OS than those treated with either alone (median OS 17.7 vs 5.7 mo, p=0.022). Median OS by treatment type is shown in Table. Conclusions: This retrospective study confirms an association between the extent of PVTT and OS in a Western HCC cohort. Patients with adequate hepatic reserve may benefit from more aggressive multi-modality treatment approaches. OS by PVTT extent and treatment modality.