BACKGROUND: Antiretroviral therapy is a proven medication given for Human Immunodeficiency Virus positive individuals. However, first-line antiretroviral treatment failure becomes a public health issue and early detection of treatment failure is crucial for timely actions. Therefore, this study aimed to identify the predictors of time to first-line antiretroviral treatment failure among adult patients living with HIV in public health facilities of Arba Minch Town. METHODS: Institution-based retrospective cohort study was employed among 396 adult patients that were selected using simple random sampling. The data on relevant variables were extracted from patient medical cards. Bi-variable and multi-variable Cox proportional hazard regression analyses were used to identify predictors. RESULTS: The median survival time was 21 months. Substance use (AHR=2.94, 95% CI=1.62 to 5.32), disclosure status (AHR=1.98, 95% CI=1.03 to 3.79), time since HIV diagnosis (AHR=2.19 95% CI=1.01 to 4.79), WHO clinical stage (AHR=2.02, 95% CI=1.02 to 4.00), opportunistic infection (AHR=2.27, 95% CI=1.23 to 4.19), nutritional status (AHR=3.78, 95% CI=1.99 to 7.17), functional status (AHR=2.71 95% CI=1.33 to 5.51), CD4 count (AHR=1.99, 95% CI=1.05 to 3.75), and adherence level (AHR=1.99, 95% CI=1.05 to 3.76) were independent predictors of time to first line ART treatment failure.CONCLUSION: History of substance use, lack of disclosure status, time since HIV diagnosis, advanced WHO clinical staging, low CD4 counts, opportunistic infection, functional status, poor adherence to ART and under-nutrition affect the time to first-line treatment failure among adult patients living with HIV. Therefore, preventive interventions, and information and counseling focusing on high risk groups of HIV infected adult are very important. KEYWORDS: Time to first line treatment failure, Poor adherence, Under-nutrition, Arba Minch