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The cost-effectiveness of the second-generation direct-acting antivirals (DAA) has received considerable attention; however, their effect on wider societal costs has remained relatively unexplored. The aim of this study was to investigate the effect the new drugs have on sick leave compared to older treatment paradigms. This retrospective study utilized Swedish registry data to identify three cohorts: (a) patients treated with ribavirin and/or peginterferons (peg-IFN) during 2005-2011; (b) patients treated with the first generation of DAAs and ribavirin and/or peg-IFN 2011-2013; and (c) patients treated with the new generation of DAAs 2014-2018. Individual-level data on sick leave and early retirement were used to compare days away from work the year prior to the year following treatment initiation. A difference-in-difference model was estimated to test for differences between the cohorts adjusting for age and gender. Days away from work prior to treatment initiation was similar in the cohorts: 106, 85 and 94 days in cohorts 1 to 3. After treatment initiation, the number of days away from worked increased in cohort one and two to 150 and 140 days, while it remained similar in cohort three (88 days). The monetary value of the avoided sick leave was 7000-10 000 €. In conclusion, patients treated with second-generation DAAs without peg-IFN had fewer days of sick leave in the year following treatment initiation compared to older treatments. Some caution is advised when interpreting the absolute figures due to potential heterogeneity between cohorts as they were treated at different points in time., (© 2020 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)