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Abstract Objective This study was conducted to determine the rate of initial second-line ART regimen change and its predictors among adults living with HIV in Amhara region. A retrospective follow-up study was conducted between February, 2008 and April, 2016 at eight governmental hospitals of Amhara region. Person-times and Cox proportional hazard model were fitted to determine the rate and to identify the significant predictors of second-line treatment regimen change. Results A total of 897 records of patients were analyzed. The overall rate of initial second-line drug regimen change was 24.2 per 100 person years. The rate of regimen change was decreased for patients with formal education (HR: 0.77, 95% CI 0.61–0.97), under WHO clinical stage-III (HR: 0.57, 95% CI 0.45–0.73), and WHO clinical stage-IV (HR: 0.64, 95% CI 0.43–0.96). Patients who were taking CPT (HR: 2.05, 95% CI 1.45–2.89) had an increased rate of regimen change. Furthermore, the rate of regimen change was decreased for patients who were switched to second-line treatment due to virological failure (HR: 0.36, 95% CI 0.25–0.53), and due to drug toxicity (HR: 0.48, 95% CI 0.28–0.81). Therefore, addressing significant predictors to maximize the durability on the initial regimen among ART clients is essential.