Introduction: Highly active antiretroviral therapy (HAART) played a critical role in the medical management of HIV infected individuals by restoring the immune function and minimizes HIV related complications. Though many studies support this conclusion, as the use of HAART increases, the issue of drug resistance and subsequent treatment failure presenting as one or more of clinical, immunological or virological ART failure appears as a challenge. Objective: This study aimes to assess prevalence of first line ART treatment failure and its associated factors among children on ART at Felege Hiwot Comprehensive Specialized Hospital (FHCSH), North WEST Ethiopia, 2022. Methods: An institution-based cross-sectional study was conducted on children taking ART at Felege Hiwot Comprehensive Specialized Hospital by including 308 Under 18 Children on ART who took for at least six months. Data was collected from the patients’ medical records and entered to computer to analyze by SPSS version 25 and Binary Logistics regression models (Bivariate and multivariable analysis) was carried out to see the association of each independent variable on the dependent variable. Results: Data were extracted and analyzed from 308 children’s medical cards. 160 (51.9%) were males and majority of children were in the age group of 10 to 17 years. The mean age at time of study was 13.97years and about 79.5% were live in urban area.The prevalence of first line ART failure was 16.9%. Poor adherence , low CD4+count and live in urban area were statistically significantly associated factors of first line ART failure with AOR: = 5.814, 95% CI (1.201-28.149), P=0.029, 15.614, 95% CI (3.434-71.002), P=0.001 and 0.106, 95% CI (0.023- 0.495), P=0.004, respectively. Conclusion: In this study, the burden of first line ART treatment failure was higher(16.9%) compared to WHO virological criteria for first line ART treatment failure which must be less than 10%. Poor adherence, low CD4+count and live in rural area were significant risks for first line ART treatment failure. Therefore, this study indicates the need for much effort from ART clinic staffs to have strict monitoring and follow up by using enhanced adherent cancelling on signifcant risk factors to have good drug adherence and to decrease treatment failure. Key Words: Children, Antiretroviral therapy, Treatment failure, Felege Hiwot Hospital.