Background: Antiretroviral treatment (ART) change should be done when necessary to save treatment options. Considering ART experience and available treatment options is vital to approach patients, and substitution requires adjustment in learning the new medication about the treatment dosing, time of intake, and dealing with many individual-based inconveniences, which might be challenging and reason for non-adherence. Determining the reasons for ART change may help to minimize the risk factors. This leads to decreased regimen change, treatment failure, drug resistance, and improved patients’ quality of life. However, little was identified about incidence and predictors of initial regimen change in the study area. This study was aimed to assess incidence and predictors of initial Antiretroviral therapy regimen change among adult patients. Method: An institutional-based retrospective cohort study was conducted among 446 adult HIV patients who started ART from January 2015 to December 2020. A simple random sampling technique was used to select patient records using computer-generated random numbers. Data extraction tools were used to collect data from patient's charts. Kaplan–Meier and log-rank methods were used to estimate the median follow-up time and compare regimen change survival curves between the different categories of explanatory variables. Bivariate and multivariate Cox proportional hazard models were used to identify predictors of initial regimen change. Result: The overall incidence rate of initial regimen change was 13.92 (95 % CI 12.36-15.72) per 100 person-years observation. Age 25-34 years (AHR=0.65 95 % CI:0.45-0.93), being male (AHR=1.6195 % CI 24-2.07), duration on regimen < 12months (AHR=0.21 95 % CI (0.1-0.43), Nevirapine on initiation (AHR=10.37(1.71-100.46), and Efavirenz on initiation (AHR=12.14 95% CI:1.7-88.74) were significant predictors of initial regimen change. Conclusions: The incidence rate of an initial ART regimen change was found to be high. Male, age 35-44, duration on regimen <12months on ART, EFV on an initial regimen, and NVP on initial regimen were independent predictors of regimen change. Consideration should be given to patients at age 25-34 years, male, duration on regimen < 12months, and EFV or NVP at the initiation.