Drug-drug interactions (DDIs) influence the effectiveness of medication and thus determine the treatment outcomes of diseases managed with pharmacotherapy. This study aimed to determine the prevalence, severity, and factors associated with potential drug-drug interactions in prescriptions presented at private pharmacies in Mbarara city. DDIs were identified and classified basing on risk and severity using Lexicomp drug interaction database. STATA version 13 was used to analyze the collected data. Descriptive statistics were used to summarize the severity of potential DDIs identified. Bivariate and multivariate logistic regression was employed to identify different factors associated with the presence of potential DDIs. A total of 295 prescriptions from 18 private pharmacies were studied and the prevalence of clinically significant potential DDIs was 37.6%. About half (149, 50.5%) of the patients were females, the majority (199, 67.5%) were adults 18-59 years of age whereas most (208, 70.5%) had a comorbid condition. Over one half (162, 54.9%) of the prescriptions were received from hospitals and majority of the prescriptions had 4 drugs prescribed (n= 175, 59.32%). Having one or more comorbidities and prescribing of therapeutic drug categories including anti-fungal, antihypertensives, analgesics, or corticosteroids were significantly associated with potential DDIs. The prevalence of potential drug-drug interactions in outpatient setting in Mbarara city was high and majority of the potential DDIs were of moderate severity. Having 1 or more comorbidities and prescribing of therapeutic drug categories including antifungals, antihypertensives, analgesics, or corticosteroids were significantly associated with potential DDIs.