BackgroundRegimen change is a major challenge for the sustainability of human immunodeficiency virus (HIV) treatment program. In a resource limited setting where treatment options are limited, designing strategies to increase the durability of original regimen are essential. However, information’s on rate of initial regimen change and its predictors is scarce in Ethiopia. Therefore, the purpose of this study was to assess the rate of initial highly active anti retroviral therapy (HAART) regimen change and its predictors among adult HIV patients at the University of Gondar Referral Hospital, Northwest Ethiopia.MethodsAn institutional based retrospective follow up study was conducted among 410 adult HIV patients started HAART from January 2010 to December 2014. Simple random sampling technique was used to select patient records using computer generated random number. Data were collected from patient chart using data extraction tool. The Kaplan–Meier curve was used to estimate the median duration of regimen change. Life table was used to estimate the cumulative survival for initial regimen change and log rank test to compare regimen change survival curves between the different categories of explanatory variables. Bivariate and multivariate Cox proportional hazard model were used to identify predictors of initial regimen change.ResultsThe overall incidence rate of initial regimen change was 10.11 (95 % CI 8.29, 12.6) per 100 person years (PY). Baseline WHO clinical stage III (AHR = 1.92, 95 % CI 1.12–3.35), occurrence of tuberculosis (TB) on the initial regimen (AHR = 8.33, 95 % CI 4.47–15.53), side effect on the initial regimen (AHR = 25.27, 95 % CI 15.12–42.00) and co-medication with ART (AHR = 2.5, 95 % CI 1.46–4.34) were significant predictors of initial regimen change.ConclusionsThe rate of initial HAART regimen change was found to be high. Having WHO clinical stage III, co-medication with ART, occurrence of tuberculosis and side effect on initial regimen were independent predictors of regimen change. Hence, close follow-up and screening of patient for side effect and tuberculosis is important.