A double-blind, phase IIb, randomized controlled trial of the malaria vaccine RTS,S/AS02A showed an efficacy of 45.0% in reducing the force of infection for Plasmodium falciparum and of 29.9% in reducing incidence of clinical malaria in children 1-4 years of age in Manhiça, Mozambique. We simulate this trial using a stochastic model of P. falciparum epidemiology, and the setting-specific seasonal pattern of entomologic inoculations as input. The simulated incidence curve for the control group was comparable with that observed in the trial. To reproduce the observed efficacy in extending time to first infection, the model needed to assume an efficacy of 52% in reducing the force of infection. This bias arises as a result of acquired partial immunity against blood stages, thus suggesting an explanation for the lower efficacy observed in a previous trial in semi-immune adult men in The Gambia. The shape of the incidence of infection curve for the vaccine cohort in Manhiça indicates that the vaccine provides incomplete protection to a large proportion of the vaccinees, rather than offering complete protection to some recipients and none to others. This behavior is compatible with a model of no decay in efficacy over the six-month surveillance period of the trial. The model accurately reproduced the lower efficacy against clinical disease than against infection. In the simulations this finding resulted from loss of acquired clinical immunity as a result of a reduction in the force of infection in the vaccinated cohort. The model also predicted greater efficacy against severe diseases than against clinical disease. The success of the simulation model in reproducing the results of the Manhiça trial encourages us to apply the same model to predict the potential public health and economic impact if RTS,S/AS02A were to be introduced into the existing expanded program on immunization.