Infections with variant Creutzfeldt-Jakob disease (vCJD) have almost exclusively occurred in young patients, but the reasons for this age distribution are uncertain. Our data suggest that the pathogenesis of many peripherally acquired transmissible spongiform encephalopathy (TSE) agents is less efficient in aged individuals. Four vCJD cases linked to transfusion of vCJD-contaminated blood or blood products have been described. Three cases occurred in elderly patients, implying that intravenous exposure is more efficient in aged individuals than other peripheral routes. To test this hypothesis, young (6 to 8 weeks old) and aged (600 days old) mice were injected intravenously with a TSE agent. In aged and young mice, the intravenous route was more efficient than other peripheral routes of TSE agent exposure. However, in aged mice, disease pathogenesis was significantly reduced. Although most aged mice failed to develop clinical disease during their life spans, many showed histopathological signs of TSE disease in their brains. Thus, the effects of age on intravenous TSE pathogenesis may lead to significant levels of subclinical disease in the population. After peripheral exposure, many TSE agents accumulate upon follicular dendritic cells (FDCs) in lymphoid tissues before they infect the brain. In aged spleens, PrP(C) expression and TSE agent accumulation upon FDCs were reduced. Furthermore, the splenic marginal zone microarchitecture was substantially disturbed, adversely affecting the delivery of immune complexes to FDCs. This study is the first to suggest that the effects of aging on the microarchitecture and the function of the splenic marginal zone significantly influence the pathogenesis of an important pathogen.