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Background and Aims: Hepatitis C virus (HCV) management in Inflammatory Bowel Disease (IBD) is uncertain. The ECCO guidelines 2021 recommended HCV treatment but warn about the risk of IBD reactivation. We aimed to evaluate 1) the effectiveness and safety of direct-acting antivirals (DAAs) in IBD; 2) the interaction of DAAs with IBD drugs., Methods: Multicentre study of IBD patients and HCV treated with DAAs. Variables related to liver diseases and IBD, as well as adverse events (AEs) and drug interactions, were recorded. McNemar's test was used to assess differences in the proportion of active IBD during the study period., Results: We included 79 patients with IBD and HCV treated with DAAs from 25,998 IBD patients of the ENEIDA registry. Thirty-one (39.2 %) received immunomodulators/biologics. There were no significant differences in the percentage of active IBD at the beginning (n = 11, 13.9 %) or at the 12-week follow-up after DAAs (n = 15, 19 %) (p = 0.424). Sustained viral response occurred in 96.2 % (n = 76). A total of 8 (10.1 %) AEs occurred and these were unrelated to activity, type of IBD, liver fibrosis, immunosuppressants/biologics, and DAAs., Conclusions: We demonstrate a high efficacy and safety of DAAs in patients with IBD and HCV irrespective of activity and treatment of IBD., Competing Interests: Conflict of interest Dr. A. Martín‐Cardona has received financial support for conference attendance, educational activities, and research support from Abbvie, Biogen, Faes Farma, Ferring, Jannsen, MSD, Pfizer, Takeda, Dr. Falk Pharma and Tillotts. Dra. MJ Casanova has received research or education funding from Pfizer, Takeda, Janssen, MSD, Ferring, Abbvie, Biogen, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi and Norgine. Dr. C. González-Muñoza has received financial support for travel and educational activities from Pfizer, Takeda, MSD, Norgine, Janssen, Tillots, and Kern Pharma. Dra. M. Piqueras has served as a speaker or has received research or education funding from Takeda, Abbvie and Janssen. Dr. I. Rodríguez-Lago has received financial support for travelling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Celltrion, Chiesi, Danone, Dr. Falk Pharma, Ferring, Faes Farma, Janssen, Galapagos, MSD, Otsuka Pharmaceutical, Pfizer, Roche, Takeda, and Tillotts Pharma. Dra. N. Manceñido Marcos has served as a speaker and consultant for or has received financial support for educational activities from Janssen, AbbVie, Pfizer, Takeda, Ferring, Faes Farma, Dr. Falk Pharma and Tillotts Pharma. Dra. B. Sicilia has received research or education funding or advisory fees from Abbvie, FAES, Chiesi, Dr. Falk, MSD, Tillots Pharma, Khern Pharma, Janssen, Pfizer and Takeda. Dr. E. Domènech has served as a speaker or has received research or education funding or advisory fees from AbbVie, Adacyte Therapeutics, Biogen, Celltrion, Galapagos, Gilead, Imidomics, Janssen, Kern Pharma, MSD, Pfizer, Roche, Samsung, Takeda and Tillots. Dra. M. Esteve has received support for conference attendance and research support from Abbvie, Biogen, Faes Farma, Ferring, Jannsen, MSD, Pfizer, Takeda, and Tillotts. The remaining authors report no conflicts of interest related to this manuscript., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)