A prospective study of 458 infants from Kampala, Uganda, who were followed from birth to 48 months of age, documented a reduced risk of malaria in children infected with HIV-1. Included in the analysis were 77 HIV-infected children, 232 seroreverters, 125 HIV-negative children born to uninfected mothers, and 24 children of indeterminate HIV status. Thick and thin blood smears for malaria were obtained from children with fever. 51% of all children had at least 1 positive malaria smear during the study period, for a total of 653 documented malaria episodes. HIV-infected children had 3.5 episodes of malaria per 100 child months of observation compared with 5.0 episodes among seroreverters and 5.5 episodes among seronegative children. The relative rates of occurrence of malaria were 1.0 (95% confidence interval [CI], 0.8-1.2) in seroreverters and 1.1 (95% CI, 0.9-1.4) There was an increase in smears positive for malaria parasitemia among seroreverters (risk ratio, 1.5; 95% CI, 1.1-1.9) and HIV-negative controls (risk ratio, 1.6; 95% CI, 1.2-2.2) compared with HIV-infected children. Parasitemia levels during episodes of malaria were not significantly different between groups. Although the HIV-infected children had fewer episodes of malaria, they had a greater percentage of severe malaria episodes than controls and more frequent hospitalizations and blood transfusions per acute malarial episode. Within the HIV-positive group, mortality and progression to AIDS were delayed (although not significantly) among children who had malaria compared with those without malaria. It is possible that HIV-1 suppresses Plasmodium infection by creating a milieu that is suboptimal for parasite growth.