Objective: This study aims to explore the prevalence and associated risk factors for potential drug-drug interactions (pDDIs) in prescriptions among outpatients with depression, and report the widespread rel-evant drug interactions. Methods: The cross-sectional retrospective study was conducted on outpatients in a psychiatric hospital. We included prescriptions of outpatients with a principal diagnosis of depression from April 1st to June 30th in 2021. The patients were >= 18 years old and treated with two or more drugs including at least one psychotropic drug. pDDIs were detected and identified mainly using Medscape's drug interactions checker. Gender, the number of concomitant drugs, age and diagnosis were analysed as potential risk fac-tors for the occurrence of pDDIs by logistic regression. Results: A total of 13,617 prescriptions were included in the present analysis, and 4222 prescriptions (31.0%) were at risk of 8557 pDDIs. The risk of pDDIs in patients who were prescribed 4-6 drugs (OR: 3.49, 95% CI: 3.11-3.91, p < 0.001) or 7 or more drugs simultaneously (OR: 7.86, 95% CI: 1.58-39.04, p < 0.05) increased compared with patients prescribed 2-3 drugs. Patients with recurrent depressive dis-orders (OR: 1.18, 95% CI: 1.02-1.36, p < 0.05) had an increased risk of pDDIs compared with patients with depressive episodes. In terms of severity of pDDIs identified by Medscape's drug interactions checker, 0.7%, 16.4%, 77.5% and 5.4% of pDDIs were classified as contraindicated, serious, monitor closely and minor, respectively. The most common pDDI was escitalopram + quetiapine (374 prescriptions), which was classified as serious and monitor closely due to different mechanisms of interaction. Increased cen-tral nervous system (CNS)-depressant effect was the most frequent potential clinical adverse outcome of the identified pDDIs. Conclusions: pDDIs in outpatients with depression were prevalent in this retrospective study. The num-ber of concomitant drugs and severity of the disease were important risk factors for pDDIs. The pDDIs of the category monitor closely were the most common, and the CNS-depressant effect was the most fre-quent potential clinical adverse outcome.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).