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Background and Aims: The treatment of hepatocellular carcinoma (HCC) is undergoing a historic transformation with the approval of several new systemic therapies in the last few years. This study aimed to examine the impact of this changing landscape on survival and costs in a Western nationwide, real-world cohort., Methods: A nationwide representative claims database (InGef) was screened for HCC cases between 2015 and 2020. Survival in an era with only sorafenib (period A, January 2015 to July 2018) and after approval of lenvatinib and other systemic treatments (period B, August 2018 to December 2020) was analysed. Health care costs were assessed., Results: We identified 2876 individuals with HCC in the study period. The proportion of patients receiving systemic therapy increased significantly over time, from 11.8% in 2015 to 15.1% in 2020 (p < 0.0001). The median overall survival in period B was 6.5 months (95% confidence interval [CI]: 4.9-8.9) and in period A was 5.3 months (95% CI: 4.5-6.3; p = 0.046). In period B, the median overall survival with lenvatinib was 9.7 months (95% CI: 6.3-18.4) versus 4.8 months with sorafenib (95% CI: 4.0-7.1, p = 0.008). Costs for prescription drugs per patient increased from €6150 in 2015 to €9049 in 2020 (p < 0.0001), and costs for outpatient care per patient increased from €1646 to €2149 (p = 0.0240)., Conclusion: The approval of new systemic therapies resulted in a survival benefit in patients with HCC. The magnitude of the effect is modest and associated with a moderate increase in health costs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: N.B.K. has received reimbursement of meeting attendance fees and travel expenses from EISAI and a lecture honorarium from Falk. B.M. has served as a paid consultant for Roche Diagnostics GmbH and Roche Pharma AG. D.B. and D.P.P. are employed by InGef, which received funding from LMU University for the contribution to the study. F.P.R. has received honoraria for lectures and travel support from the Falk Foundation, Gilead, Ipsen, and Novartis. A.T. has received honoraria, travel support, or/and scientific funding from Ipsen Pharma GmbH, Gilead Sciences, AbbVie Deutschland GmbH & Co. KG, F. Hoffmann-La Roche AG, Eisai GmbH, Bayer AG, Novartis AG, Intercept Pharmaceuticals, Inc., Lilly Deutschland GmbH, Alpen Pharma (Schweiz), Dr. Falk Pharma GmbH, Astra Zeneca, Sanofi-Aventis Deutschland GmbH, and Orphalan. D.R. advises Bayer and advises and has received grants from Ipsen. I.K. served as a paid consultant for Alnylam and Roche and received lecture honorarium from Takeda. U.E. has received honoraria for lectures from AstraZeneca, the Falk Foundation, IPSEN, and Novartis and travel support from AstraZeneca. She has served as advisory board or steering committee member to AstraZeneca, Bayer, EISAI, and MSD. C.M.L. has received advisory and speaker honoraria from AbbVie, AstraZeneca, Boston Scientific, CSL Behring, Eisai, Falk, Gilead, MSD, Norgine, Novartis, Roche, Shionogi, and Sobi. K.B. received a research grant from Roche Pharma AG. E.D.T. has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, Pfizer, IPSEN, and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, AstraZeneca, BMS, Bayer, Celsion, and Roche and lecture honoraria from BMS and Falk. In addition, he has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and Roche. S.M. received a research grant from Ipsen, BMBF, and the Bavarian Ministry of economic affairs and media. All the other authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)