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Increasing numbers of HIV-infected children not yet eligible for antiretroviral therapy (ART) are entering health care in Africa. We sought to characterize the risk of short-term disease progression in this population.In a cohort of HIV-infected ART-naive and -ineligible Ugandan children older than 1 year, the rates of clinical/immunologic progression within 2 years were assessed using Kaplan-Meier survival analysis and multivariate Cox proportional-hazards modeling.Among 192 children (mean age: 6.4 years, CD4%:25), 19% progressed within 2 years by World Health Organization stage 3/4 event (n = 22), death (n = 3), or World Health Organization-defined CD4 threshold for ART initiation (n = 12). Significant univariate predictors were CD4% [hazard ratio (HR) = 2.0 per 10% decrease, P = 0.005], HIV RNA level (HR = 2.4 per log10 increase, P = 0.002), male gender (HR = 2.0, P = 0.04), age < 3 years (HR = 3.7, P = 0.001), CD4 activation (%CD4+ CD38+ HLADR+) (HR = 1.6 per 10% increase, P = 0.05), and CD8 activation (%CD8+ CD38+ HLADR+) (HR = 1.3 per 10% increase, P = 0.05] (HR = 1.3, P = 0.5). In multivariate analysis, CD4% (HR = 2.0, P = 0.034), HIV RNA level (HR = 1.8, P = 0.013), and age < 3 years (HR = 3.0, P = 0.008) were independently predictive. Children with HIV RNA >105 copies per milliliter and CD4% <25 had progression rates of 29% (1 year) and 34% (2 years).Even with frequent CD4 monitoring, HIV-infected Ugandan children experienced significant clinical events while ineligible for ART per WHO 2006 guidelines.