Background : Human immunodeficiency virus (HIV) infection is a public health concern globally. The numbers of people living with HIV worldwide in 2018 was estimated at 37.9 million; from those, 1.7 million are children. Globally, 62% of the 37.9 million people were receiving Antiretroviral treatment (ART); 53% had achieved viral suppression. This study aimed to assess the incidence and predictors of Antiretroviral treatment failure among children in Kolfe Keranyo sub-city, Addis Ababa, Ethiopia. Methods : An institution-based retrospective cohort study was conducted among 250 children who were enrolled to first-line Antiretroviral treatment from January 2013 to May 2020 in Kolfe Keranyo sub-city. Data was collected by using data extraction checklist and data were extracted by reviewing children’s medical chart and electronic database. Kaplan–Meier method was used to estimate the probability of treatment failure. During bivariable analysis variables with p-value < 0.25 were taken for multivariable Cox regression analysis to assess predictors of treatment failure. Statistically significant association was declared at p-value < 0.05 with 95% confidence interval. Result : The overall treatment failure rate within the follow-up period was 17.2%. This study also found that the overall incidence density rate was 3.45% (95% CI: 2.57-4.67) per 1000 person-month observation. Infant prophylaxis for PMTCT (AHR: 3.59, 95% CI: 1.65-7,82), drug substitution (AHR: 0.18, 95% CI: 0.09-0.37), AZT/3TC/NVP based regimen (AHR: 2.27, 95% CI: 1.14-4.25), and more than 3 episodes of poor ART adherence (AHR: 2.27, 95% CI: 1.17-4.38) were found to be predictors of treatment failure among children. Conclusion : High proportion of treatment failure was found among children on first-line ART in Kolfe Keranyo sub-city, Addis Ababa. Infant prophylaxis for PMTCT, drug substitution, initial regimen, and poor ART adherence were found to be predictors of first-line ART treatment failure. Close follow-up of children on medication adherence and effective trainings to health care professionals need to be considered.