Immunity to Plasmodium falciparum develops slowly in areas of endemicity, and this is often ascribed to poorly immunogenic or highly variant parasite antigens. However, among populations newly exposed to malaria, adults acquire immunity more rapidly than children. We examined the relationship between pubertal development and resistance to P. falciparum. During two transmission seasons in western Kenya, we treated the same cohort of young males to eradicate P. falciparum and then obtained blood smears each week for 4 months. We determined pubertal development by Tanner staging and by levels of dehydroepiandrosterone sulfate (DHEAS) and testosterone in plasma. In multivariate and age-stratified analyses, we examined the effect of pubertal development on resistance to malaria. In both seasons (n ‫؍‬ 248 and 144 volunteers, respectively), older males were less susceptible than younger males. Age-related decreases in the frequency and density of parasitemia were greatest during puberty (15-to 20-year-olds). DHEAS and testosterone were significant independent predictors of resistance to P. falciparum parasitemia, even after accounting for the effect of age. Fifteen-to 20-year-old males with high DHEAS levels had a 72% lower mean parasite density (P < 0.01) than individuals with low DHEAS levels. Similarly, 21-to 35-year-old males with high DHEAS levels had a 92% lower mean parasite density (P < 0.001) and 48% lower frequency of parasitemia (P < 0.05) than individuals with low DHEAS levels. These data suggest that the long period needed to attain full immunity could be explained as a consequence of host development rather than as the requirement to recognize variant or poorly immunogenic parasite antigens.Plasmodium falciparum malaria is a leading cause of morbidity and mortality in developing countries, infecting hundreds of millions of individuals and killing up to 1 million children in sub-Saharan Africa each year (2). This death toll will rise as drug-resistant parasites spread (35), and meanwhile the promise of a broadly effective malaria vaccine remains unfulfilled despite important technological advances (27). Residents of areas of endemicity develop protective immunity that limits parasitemia and disease, providing a model for vaccine development, but the responses conferring naturally occurring protection have not been elucidated.P. falciparum infection is more frequent and severe in children than in adults (23; reviewed in reference 4), and resistance is acquired over years of exposure. The long period required to develop resistance has supported the widely held views that the parasite is poorly immunogenic or that protective immunity is strain specific and requires exposure to the many parasite variants circulating in a community (10,14). The recent observation that adult migrants to an area of endemicity acquire resistance more rapidly than their younger counterparts implicates host development in decreased susceptibility to P. falciparum (5, 7). In an area of holoendemicity in Kenya, where malaria is ubiqu...