The Ethiopian Paediatric HIV Cohort was established to identify clinical and laboratory predictors of virological treatment failure to ultimately develop a clinical–immunological prediction rule with area under the curve of >0.80 for detecting first-line antiretroviral therapy failure (ARTF). It will also assess the performance of the current WHO guidelines for detection of first-line ARTF in children. Using a prospective cohort design, HIV-infected children and adolescents below the age of 18 years are followed every 6 months with a set of clinical and laboratory parameters at 6 hospitals in southern Ethiopia. From October 2015 through April 2016, 628 children have been enrolled. The cohort will be completed in September 2017. The successful completion of this study will allow for better targeting of viral-load testing to those at highest risk in resource-poor settings and provide clinicians and policymakers with a practical prediction rule.