ObjectiveMany medications have potential interactions with other drugs or substances when prescribed together. This study was intended to investigate the extent of poly-pharmacy, event of drug–drug interactions and associated ADRs in Adama Referral Hospital, Oromia regional State, Ethiopia to create awareness of potential drug interactions and for development of clinical strategies to prevent the occurrence of DDIs.MethodsA retrospective study was done at Adama Referral hospital, Adama city, Ethiopia during March–May 2014. Medscape online were used for DDIs and ADRs detection purposes.ResultsThe average number of drugs prescribed per person (encounter) in this study was found to be 2.6, showing the presence of poly-pharmacy prescribing practice based on WHO recommendations (1.4–2.4). With 788 medications prescribed, 267 DDIs were found in this study and 62 (20.7%) were categorized as serious DDIs, 95 (31.7%) as significant DDIs, and 110 (36.7%) as minor DDIs. DDIs occurrence was also categorized according to the mechanisms, Pharmacokinetic and pharmacodynamic interactions; the highest frequency of DDIs was observed in 85 (31.8%), attributable to metabolism interaction followed by Antagonistic effect in 51 (21.4%), and Synergistic/Additive effect in 44 (16.5%). It was observed that serious DDIs most often caused possible cardiovascular ADRs.ConclusionsThe results of the study showed the high number of drugs per person compared to the WHO-reported average number of drugs per person and occurrence of DDIs associated with severe cardiovascular risk ADRs in the Adama Referral Hospital. This study recommends that the drug information center facilities and drug prescription validation is done by the pharmacist and the development of pharmacotherapeutic guidelines supporting selection of drugs in Ethiopian hospitals for preventing DDIs and ADRs.