Objectives: Direct-acting antivirals (DAAs) for treatment of chronic hepatitis C virus (HCV) infection can cause drug–drug interactions (DDIs) with combination antiretroviral therapy (cART) and non-cART co-medication. We mapped how physicians manage DDIs between DAAs and co-medication and analysed treatment outcomes. Methods: Data were prospectively collected as part of the ATHENA HIV observational cohort and retrospectively analysed. Dutch patients with HIV/HCV coinfection who initiated treatment with DAAs between January 2015 and May 2016 were included. Co-medication 3 months prior to and during DAA therapy was identified. Potential DDIs with the DAAs were checked using http://hep-druginteractions.org. DDIs were categorized as: (1) no interaction expected; (2) potential interaction; (3) contra-indication; (4) no recommendation. These categories were used to determine which patients switched or had a DDI during DAA therapy with co-medication. Results: A total of 423 patients were treated with DAAs, of whom 418 (99%) used cART and 251 (59%) used non-cART co-medication. Before commencing DAA treatment, in 17 of 84 (20%) patients the non-cART co-medication which could result in a category 2/3 DDI was discontinued before DAA initiation, including two of six (33%) prescriptions of category 3 drugs. A total of 196 of 418 (47%) patients had a category 2/3 DDI between their DAA regimen and cART. Category 2/3 DDIs were prevented by switching cART in 78 of 147 (53%) and 47 of 49 (98%) patients. Overall, 367 of 423 (87%) patients have achieved a sustained virological response (33 in follow-up). Conclusions: Prescription patterns suggest that physicians are aware of potential DDIs between co-medication and DAAs, in particular potential DDIs with cART. Greater awareness is needed concerning category 3 interactions between non-cART co-medication and DAAs.