Background Many resource-limited countries rely on clinical and immunologic monitoring without routine virologic monitoring of HIV-infected children receiving highly active antiretroviral therapy (HAART). We assessed whether HIV viral load (VL) had independent predictive value in the presence of immunologic and clinical data for the occurrence of new World Health Organization (WHO) stage 3 or 4 events (WHO events) among HIV-infected children receiving HAART in Latin America. Methods The NICHD International Site Development Initiative (NISDI) Pediatric Protocol is an observational cohort study designed to describe HIV-related outcomes in infected children. Eligibility criteria for this analysis included perinatal infection, age <15 years, and continuous HAART for ≥6 months. Cox proportional hazards modeling was used to assess the time to new WHO events as a function of immunological status, VL, hemoglobin and potential confounding variables; laboratory tests repeated during the study were treated as time-varying predictors. Results The mean follow-up was 2.5 years; new WHO events occurred in 16% of 584 children. In proportional hazards modeling, most recent VL > 5000 copies/mL was associated with a nearly doubled risk of developing a WHO event (adjusted hazard ratio=1.81, 95% CI 1.05–3.11; p=0.033), even after adjustment for CD4-defined immunosuppression, hemoglobin level, age and body mass index. Conclusions Routine virologic monitoring, using the WHO virologic failure threshold of 5,000 copies/mL, adds independent predictive value to immunologic and clinical assessments for identification of children receiving HAART who are at risk for significant HIV-related illness. To provide optimal care, periodic virologic monitoring should be considered for all settings providing HAART to children.