BACKGROUND: Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure. METHODS: We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum We jointly quantified individual heterogeneity in the risk of infection and the development of immunity against infection and clinical disease. RESULTS: Results showed significant heterogeneity in the hazard of infection and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95% confidence interval [CI], 0%-12%) for each additional year of age and by 2% (95% CI, 1%-3%) for each additional prior infection. Children randomly assigned to receive dihydroartemisinin-piperaquine for treatment appeared to develop immunity more slowly than those receiving artemether-lumefantrine. CONCLUSIONS: Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity.