OBJECTIVE: To assess patterns of morbidity and associated factors in late infancy and early childhood among human immunodeficiency virus (HIV)-infected and -uninfected African children. DESIGN: Prospective study. SETTING: The Queen Elizabeth Central Hospital, Blantyre, Malawi. PARTICIPANTS: Children with known HIV status from an earlier perinatal intervention trial were enrolled during the first year of life and followed to approximately 36 months of age. OUTCOME MEASURES: Morbidity and mortality information was collected every 3 months by a questionnaire. A physical examination was conducted every 6 months. Blood to determine CD4(+) values was also collected. Age-adjusted and Kaplan-Meier analyses were performed to compare rates of morbidity and mortality among infected and uninfected children. RESULTS: Overall, 808 children (190 HIV-infected, 499 HIV-uninfected but born to infected mothers, and 119 born to HIV-uninfected mothers) were included in this study. Of these, 109 died during a median follow-up of 18 months. Rates of childhood immunizations were high among all children (eg, lowest was measles vaccination [87%] among HIV-infected children). Age-adjusted morbidity rates were significantly higher among HIV-infected than among HIV-uninfected children. HIV-infected children were more immunosuppressed than were uninfected children. By 3 years of age, 89% of the infected children died, 10% were in HIV disease category B or C, and only approximately 1% were without HIV symptoms. Among HIV-infected children, median survival after the first occurrence of acquired immunodeficiency syndrome-related conditions, such as splenomegaly, oral thrush, and developmental delay, was <10 months. These same conditions, in addition to frequent bouts of fever, were the main morbidity predictors of mortality. CONCLUSIONS: The frequency of diseases was high, and progression from asymptomatic or symptomatic HIV disease to death was rapid. Management strategies that effectively reduce morbidity for HIV-infected children are needed.