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Background Advanced hepatocellular carcinoma was treated with different systemic therapies. We aimed to assess the effect of Sorafenib, Lenvatinib, and Atezolizumab+Bevacizumab on the survival of HCC, and delineate the trend of systemic therapy prescriptions in real-world practice in Hong Kong from 2011 to 2021.Methods We conducted a retrospective cohort study of HCC patients receiving systemic therapies between January 2011 and December 2021 from a territory-wide healthcare database in Hong Kong, and followed them over an 18-month period. The primary endpoints were all-cause and HCC-specific mortality.Results We identified 1268 HCC patients receiving systemic therapy (mean age 63.0±11.5 years; 75.9% male); 313 received Sorafenib, 870 received Lenvatinib, and 85 received Atezolizumab+Bevacizumab. The trend of systemic therapy prescription in Hong Kong aligned with the global trend. Atezolizumab+Bevacizumab showed the longest mean overall survival for all-cause mortality (15.6 months; 95% confidence interval [CI] 14.5-16.8) and HCC-specific mortality (17.2 months; 95%CI 16.5-18.0). Multivariate Cox regression analyses revealed a higher risk of all-cause mortality with Sorafenib (aHR 7.60; 95% CI 4.50-12.80; p <0.001). Lenvatinib (aHHR 3.40; 95%CI 2.02-5.71; p<0.001), and age of 40-59 years (aHR 1.23; 95% CI 1.01-1.50; p=0.042). For HCC-specific mortality, higher risks were associated with Lenvatinib (aHR 9.04; 95%CI 3.36-24.3; p<0.001), Sorafenib (aHR 5.82; 95%CI 2.10-16.1; p<0.001), and male sex (aHR 1.36; 95%CI 1.04-1.77; p=0.026).Conclusions Atezolizumab+Bevacizumab regimen is associated with a lower risk of all-cause and HCC-specific mortality in HCC patients, compared with Sorafenib and Lenvatinib ( IDDF2026-ABS-0537 Figure 1. Kaplan-Meier’s survival curve in all-cause and HCC-specific mortality).Abstract IDDF2026-ABS-0537 Figure 1