ABSTRACT: BACKGROUND:First-line antiretroviral treatment failure has become a public health concern in high, low and middle-income countries with high mortality and morbidity In Ethiopia, around 710,000 peoples were living with HIV and 420,000 of them were receiving ART in 2017. Little is known about the magnitude of first-line ART treatment failure and its associated factors in Ethiopia, particularly in the study area. Therefore, this study was aimed to find the magnitude of first-line ART treatment failure and its associated factors among adult patients attending ART clinic at Southwest shoa zone public hospitals. METHODS:Institutions based cross-sectional study was employed from February 1 to April 2, 2019. An interviewer administered questionnaire was used to collect data from 350 adult patients on ART using a systematic random sampling technique. The collected data were coded and entered into Epidata version 3 and exported to STATA SE version 14 for analysis. Bivariable and multivariable logistic regression was done to identify factors associated with first-line ART treatment failure. At 95% confidence level strength of association was measured using Odds ratio. Variables with a p-value of ? 0.25 in the bivariable analysis were considered as a candidate variable for multivariable analysis. To get the final variables step-wise backward selection procedure was used and those in the final model were selected at a p-value <0.05. Finally, texts, simple frequency tables, and figures were used to present the findings. RESULTS:In this study the magnitude of first-line ART treatment failure was 33.42%. Absence of baseline opportunistic infection AOR = 0.362 (95%CI0.178, 0.735), Staying on first-line ART for <5 years AOR = 0.47 (95%CI 0.252, 0.878), Nevirapine containing ART regimen AOR = 3.07 (95%CI 1.677, 5.63), Baseline CD4 count ?100 cells/mm3 AOR = 0.299 (95%CI 0.152 0.591), absence of opportunistic infections after ART initiation AOR = 0.257 (95%CI 0.142, .467), time taking greater than an one-hour to reach health facility AOR 1.85 (95%CI 1.022 3.367) were significantly associated with first-line ART treatment failure. CONCLUSION:The magnitude of first-line ART treatment failure was high in the study area. Base-line opportunistic infection, duration on first-line ART, NVP based ART, Baseline CD4 count level, OI after ART initiation, and time it takes to reach health facility were independent determinants of first-line ART treatment failure.