BackgroundCurrently, there are a few treatment options for unresectable hepatocellular carcinoma (HCC) after progression following sorafenib (SOR) therapy, but with limited benefit. The purpose of this study was to investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors (ICIs) as second-line treatment.MethodsFrom May 2018 to May 2021, a total of 93 HCCs who failed SOR treatment were included in this study and divided into TKI group (n= 37) and TKI-ICI group (n= 56). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety were estimated among the two groups. In addition, univariate and multivariate Cox regression analyses were performed for OS and PFS to identify possible prognostic factors.ResultsWith a median follow-up time of 13.7 months, the median age of patients was 56 (range, 50–64) years and most were male. All of the patients were hepatitis virus-related HCC. Both median OS (7.63 months vs 19.23 months,P< 0.001) and median PFS (2.97 months vs 8.63 months,P< 0.001) were significantly improved in the TKI-ICI group compared to the TKI group. A significant increase in DCR was demonstrated in the TKI-ICI group compared to the TKI group (83.9% vs 45.9%,P= 0.0003), although no significant difference in ORR was reported (21.4% vs 8.1%,P= 0.1552). Multivariate Cox regression analysis of OS and PFS revealed that second-line regimen was an independent protective factor affecting death and progression in HCCs after SOR failure. In addition, Child–Pugh B7 was an independent risk factor of OS. Finally, there was no significant difference in the incidence of any grade or grade 3/4 adverse events (AEs) between the two groups, and no treatment-related deaths were observed.ConclusionThis real-world study suggests that the combination of TKIs and ICIs benefits more than mono-TKIs and is well tolerated in HCCs with hepatitis virus infection after SOR failure.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-022-03324-z.