OBJECTIVES: To investigate therapeutical drugs other than antimicrobials as risk factors for the acquisition of ESBL-producing Enterobacterales (ESBL-E). METHODS: This matched case-control study is based on rectal surveillance screening data obtained during a larger trial between 2014 and 2016 upon patients' admission and at least once before discharge in eight non-ICU wards. Patients with ward-acquired ESBL-E (cases) were matched 1:1 to non-ESBL-E carriers (controls) based on ward, number of screening samples, days at risk and Charlson comorbidity index (CCI). Daily medication data were documented according to the Anatomical Therapeutic Chemical classification system. Multivariable conditional logistic regression models were used to calculate risk factors for ESBL-E acquisition. RESULTS: Of the 232 cases and 232 controls analysed, baseline characteristics such as gender (male 56.9%), median age (65 years old, IQR 52-74), number of screening samples (N = 3, IQR 2-4), days to first sample (2, IQR 1-2), days at risk (8, IQR 6-11) and CCI (4, IQR 2-6) were similar. Multivariable analysis showed that glucocorticoids, opium alkaloids and selective beta-2-adrenoreceptor agonists increased the chance to detect ESBL-E (OR 1.07, 95% CI 1.001-1.13, P = 0.047; OR 1.06, 95% CI 1.007-1.12, P = 0.027; and OR 1.31, 95% CI 1.105-1.55, P = 0.001, respectively), while antihistamines decreased it (OR 0.61, 95% CI 0.39-0.97, P = 0.034). In a sensitivity analysis, including drugs prescribed to at least 50 patients, proton pump inhibitors remained as risk factors (OR 1.049, 95% CI 1.001-1.100, P = 0.047). CONCLUSIONS: In a non-ICU setting, drugs other than antimicrobials were determined as potential independent risk factors for ESBL-E acquisition. CI - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.