Much remains unknown about the evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadiclike phenotype. To further model human-to-human vCJD prions spreading, we used a newly developed transgenic mouse model that overexpress human prion protein with methionine at codon 129, the only allele found so far in clinically vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD cases by intracerebral or intraperitoneal routes, and were analysed for transmission efficiency and strain phenotype in brain and spleen tissues. After intracerebral challenge, all infected mice developed a typical clinical disease at around 150 days and 500 days for sCJD and vCJD primary isolates, respectively. Of note, one out of four inoculated vCJD cases consistently led to the propagation of both sporadic-like and variant-like CJD prions in the brain, while vCJD-type prions invariably accumulated in the spleen. After intraperitoneal challenge, an inefficient neuroinvasion was observed, resulting in a silent infection with life-long persistence of vCJD prion in the spleen. Our findings have implications in terms of vCJD diagnosis and control. They highlight i) the potential of this agent to establish a subclinical infection in lymphoreticular tissues, thus increasing the level of concern about the risk for iatrogenic transmission; ii) the possibility that person-to-person transmission of vCJD might produce alternative disease phenotypes and that different prions might propagate in different tissues of the same individual.