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Abstract Objective This retrospective cohort study is aimed to assess reasons and predictors of regimen change from initial highly active antiretroviral therapy among 1533 Human Immunodeficiency virus-infected adult patients at the Jimma University Tertiary Hospital. Results One in two (47.7%) adults changed their antiretroviral therapy regimen. Patients who were above the primary level of education [Hazard ratio (HR) 1.241 (95% CI 1.070–1.440)] and with human immunodeficiency virus/tuberculosis co-infection [HR 1.405 (95% CI 1.156–1.708)] had the higher risk of regimen change than their comparator. Individuals on Efavirenz [HR 0.675 (95% CI 0.553–0.825)] and non-stavudine [HR 0.494 (95% CI 0.406–0.601)] based regimens had lower risk of regimen change.