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What is known and objective: Initial treatment recommendations of COVID‐19 were based on the use of antimicrobial drugs and immunomodulators. Although information on drug interactions was available for other pathologies, there was little evidence in the treatment of COVID‐19. The objective of this study was to analyse the potential drug‐drug interactions (pDDIs) derived from the medication used in COVID‐19 patients in the first pandemic wave and to evaluate the real consequences of such interactions in clinical practice. Methods: Cohort, retrospective and single‐centre study carried out in a third‐level hospital. Adult patients, admitted with suspected COVID‐19, that received at least one dose of hydroxychloroquine, lopinavir/ritonavir, interferon beta 1‐b or tocilizumab and with any pDDIs according to "Liverpool Drug Interaction Group" between March and May 2020 were included. The possible consequences of pDDIs at the QTc interval level or any other adverse event according to the patient's medical record were analysed. A descriptive analysis was carried out to assess possible factors that may affect the QTc interval prolongation. Results and discussion: Two hundred and eighteen (62.3%) patients of a total of 350 patients admitted with COVID‐19 had at least one pDDI. There were 598 pDDIs. Thirty‐eight pDDIs (6.3%) were categorized as not recommended or contraindicated. The mean value difference between baseline and pDDI posterior ECG was 412.3 ms ± 25.8 ms vs. 426.3 ms ± 26.7 ms; p < 0.001. Seven patients (5.7%) had a clinically significant alteration of QTc. A total of 44 non‐cardiological events (7.3%) with a possible connection to a pDDI were detected. What is new and conclusion: The number of pDDIs in patients admitted for COVID‐19 in the first pandemic wave was remarkably high. However, clinical consequences occurred in a low percentage of patients. Interactions involving medications that would be contraindicated for concomitant administration are rare. Knowledge of these pDDIs and their consequences could help to establish appropriate therapeutic strategies in patients with COVID‐19 or other diseases with these treatments. [ABSTRACT FROM AUTHOR]