Clinically significant drug-drug interactions reduce effectiveness of medicine or cause fatal adverse events. Although harmful drug interactions are preventable, cliniciansa recognition and detection of drug interactions isn't optimal. To assess prevalence, clinical significance and factors related to potential drug-drug interactions at medical ward of Ayder Referral Hospital, Ethiopia. A cross-sectional study was conducted to work out potential drug-drug interactions. a complete of 204 patientsa medical records were analyzed for drug-drug interaction using Micromedex drug interaction software. Data were analyzed using SPSS version 16.