PurposeData comparing the burden of the opportunistic infections among the Pre-ART and On-ART HIV-infected patients in Ethiopia are scarce. Therefore, this study aimed to compare the prevalence and predictors of opportunistic infections in Pre-ART and On-ART HIV-infected patients.MethodsA comparative cross-sectional study was conducted among adult patients infected with HIV and who were on Pre-ART or On-ART and followed up from 2012 to 2016 in Zewditu Memorial Hospital, Addis Ababa. Those patients who were infected with HIV, but not eligible for ART were categorized under Pre-ART follow-up (n=192) and those patients who started taking ART were categorized under the On-ART follow-up group (n=192). Patients were included in the study by using simple random sampling technique from the list of the patients registered in the ART follow-up database. The presence of opportunistic infections along with clinical findings and baseline laboratory data was extracted from the ART follow-up database and the medical records of the patients using a standardized checklist. Factors associated with the development of opportunistic infections were analyzed using multi-variable binary logistic regression analysis.ResultsThe overall prevalence of opportunistic infections was found to be 33.6% (95% CI; 28.9–38.5). The prevalence of opportunistic infections among the Pre-ART group (38%) was higher than On-ART group (29.2%) (P-value = 0.04). Pulmonary tuberculosis was the most common opportunistic infection observed in both Pre-ART and On-ART groups. Being in the WHO clinical Stage III (AOR = 2.1; 95% CI 1.1–3.9) or Stage IV (AOR = 3.6; 95% CI 1.7–7.7) were independent predictors for the development of opportunistic infections.ConclusionThe prevalence of opportunistic infections among the HIV-infected patients who were in Pre-ART was higher than On-ART group. This finding reinforces the need for early initiation of ART for HIV-infected patients irrespective of their CD4 counts.