BackgroundAdverse drug reactions (ADRs) are harmful and unintended reactions to medicines given at standard doses. Although the antiretroviral treatment (ART) changed the global HIV epidemic significantly, it’s associated adverse events is huge. Therefore, investigating the rate and development of ADRs of ART provides vital information for monitoring risks.MethodsRetrospective study was conducted among patients on ART from July1/2011—June 30/2016 at Felege Hiwot referral hospital. Data were collected using checklist and document review. The p-value and hazard ratio with its confidence interval was used to show presence and strength of association.ResultsA total of 602 subjects were studied. The rate of occurrence of major ADRs was 4.3/100PY. Patients with no formal and completed primary education were at higher risk of developing ADRs compared to those with higher level education [AHR = 8, 95% CI: 2.53–25.20, AHR = 4.9, 95% CI: 1.65–14.44]. The risks of ADRs among patients working in NGOs were more than four times compared to those in governmental organizations [AHR = 4.3, 95% CI: 1.42–13.31]. The risks of ADRs in WHO clinical stage II, III and IV were much higher than in stage I [AHR = 4, 95% CI: 1.33–11.93, AHR = 5.3, 95% CI: 2.02–13.79 and AHR = 7, 95% CI: 2.51–20.10] respectively. Moreover, patients didn’t receive OI prophylaxis were more three times at risk of ADRs compared to those received [AHR = 3.2, 95% CI: 1.47–7.08].ConclusionsMost of the ADRs cases were occurred within a year after initiation of ART. Educational status, occupation, advanced clinical stage and OI prophylaxis therapy were predictors ADRs. Continuous counseling for non-educated patients and clients in clinical stage II and above, and patients didn’t take OI prophylaxis need to get close follow up to prevent the associated ADRs by the concerned parties.