Treating malaria before immunizing has been standard in malaria vaccine field trials. To assess the impact of this practice on subsequent infection and disease incidence, we conducted a randomized cohort study in Bandiagara, Mali. Subjects received a treatment dose of sulfadoxine-pyrimethamine (SP) or no treatment at the beginning of the transmission season. Cumulative and age-specific incidence of clinical episodes was similar between the 2 groups, but SP treatment delayed the median time to first clinical episode from 38.5 to 68 days, and after this initial period of protection, disease incidence in the SP group quickly surpassed the incidence in the untreated group. Parasite densities during disease episodes were lower in the SP group. SP was chosen as the drug for initial parasite clearance for the following reasons: 1) it has been used in previous vaccine trials; 2) our studies have found it to have >99% efficacy in treating uncomplicated malaria in Mali compared to 85-90% efficacy for chloroquine in this area; 3) SP is the approved second-line antimalarial agent in Mali; and 4) its single-dose regimen ensures compliance when treatment is directly observed.