Background:-Drug interaction is an important therapeutic challenge among Human Immunodeficiency Virus infected patients. They are often observed in these patients because they frequently receive multiple medications. Though this may have clinical and economic impact, its prevalence is unknown in Ethiopia. So this study was aimed at addressing this issue by determining the prevalence of Co-medication and potential drug-drug interaction (PDDIs) in HIV infected patients. Method:- initially, checklist containing the relevant variables for the study was developed; ethical approval for patient medical history card (PMHC) access was requested and obtained from the hospital. Then, before the actual data collection process takes place, pre-test was done on 18 PMHCs. After assessing the check list, data of 350 HIV infected patients was reviewed retrospectively and recorded from cards using simple random sampling method. Subsequently, PDDI was assessed using Meds cape online drug interaction checker database and Drug.com (as supportive DDI checker). Then, the data was checked for completeness, entered and analyzed using Statistical Package for Social Science (SPSS) version 20 and Microsoft excel and presented using tables and figures. Result:-out of 350 HIV infected patients on HAART; only 53(15.1%) patients were not co-medicated along with Anti-Retroviral drugs. Then, a total of 2431 PDDIs were identified, and pharmacokinetic and pharmacodynamic interactions were found to occur almost in comparable frequency and almost all of the interactions were found to be moderate or minor in their severity. Conclusion:-in this study more than half of the HIV infected patients were found co-medicated and high numbers of PDDIs were identified. Accordingly, the authors of this study concluded that co-medication and PDDIs are common and, though unavoidable, since almost all of the identified PDDIs were moderate or minor in their severity, the authors’ recommend close monitoring of patients for therapeutic or toxic response.