Background and objectivesPatients with hepatocellular carcinoma (HCC) involving portal vein tumor thrombosis (PVTT) are presently lacking effective treatment options. We aimed to compare the efficacy and safety of lenvatinib with or without SBRT for HCC with PVTT.Materials and methodsThis retrospective analysis included 37 patients treated with lenvatinib in combination with SBRT and 77 patients treated with lenvatinib alone from August 2018 to August 2021. Overall survival (OS), progression-free survival (PFS), intrahepatic PFS (IHPFS) and objective remission rate (ORR) were compared between the two groups, while adverse events (AEs) was analyzed between the two groups to assess safety profiles.ResultsMedian OS, PFS and IHPFS were significantly prolonged in the combination treatment group compared with the single treatment group (median OS, 19.3 vs. 11.2 months, p < 0.001; median PFS: 10.3 vs. 5.3 months, p < 0.001; median IHPFS, 10.7 vs. 5.3 months, p < 0.001). Moreover, a higher ORR (56.8% vs. 20.8%, P < 0.001) were observed in the lenvatinib combined with SBRT group. In subgroup analyses of Vp1-2 and Vp3-4 group, median OS, PFS and IHPFS were also significantly longer in the lenvatinib combined with SBRT group than those in the lenvatinib alone group. AEs in the combined therapy group were mostly manageable and the incidence was not statistically significant compared to the monotherapy group.ConclusionLenvatinib plus SBRT had a significantly better survival benefit than lenvatinib monotherapy in the treatment of HCC patients with PVTT and was well tolerated.