We aimed to determine patient characteristics, treatment challenges, and adherence outcomes according to orphanhood status in a prospective cohort of 101 HIV+ children in rural Uganda. Orphans were older at antiretroviral initiation (P = 0.0008) and more likely to be WHO stage-4 (P = 0.03) than nonorphans. More attention to improving access to antiretrovirals in pediatric populations, especially orphans, is needed.