Clinical responses to infection or vaccination and the development of effective immunity are characterized in humans by a marked interindividual variability. To gain an insight into the factors affecting this variability, we used a controlled human infection system to study early immune events following primary infection of healthy human volunteers with blood-stage Plasmodium falciparum malaria. By day 4 of infection, a dichotomous pattern of high or low expression of a defined set of microRNAs (miRs) emerged in volunteers that correlated with variation in parasite growth rate. Moreover, high-miR responders had higher numbers of activated CD4+ T cells, and developed significantly enhanced antimalarial antibody responses. Notably, a set of 17 miRs was identified in the whole blood of low-miR responders prior to infection that differentiated them from high-miR responders. These data implicate preexisting host factors as major determinants in the ability to effectively respond to primary malaria infection.