The cumulative incidence of switching to second-line antiretroviral therapy (ART) among children is quantified in an international cohort collaboration. Individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 was obtained from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. At the data cutoff of Sept 16, 2015, the CIPHER dataset included 182,747 children with HIV. Of these, 93,351 were eligible with 83,984 (90·0%) from sub-Saharan Africa. Findings revealed wide variations in the incidence of switching to second-line ART across monitoring strategies. Multivariable analyses suggested patient-level factors such as male sex, older age at ART initiation, and initial NNRTI-based regimen which were associated with an increased likelihood of switching. Cohort-level factors associated with increased likelihood of switching comprised higher-income country and routine or targeted monitoring of CD4 and viral load. The findings suggest a probability of an increase in demand for pediatric second-line ART formulations with the scale-up of viral load monitoring.