The early replication of some orally-acquired prion strains upon stromal-derived follicular dendritic cells (FDC) within the small intestinal Peyer's patches is essential to establish host infection, and for the disease to efficiently spread to the brain. Factors that influence the early accumulation of prions in Peyer's patches can directly influence disease pathogenesis. The host's immune response to a gastrointestinal helminth infection can alter susceptibility to co-infection with certain pathogenic bacteria and viruses. Here we used the natural mouse small intestine-restricted helminth pathogen Heligmosomoides polygyrus to test the hypothesis that pathology specifically within the small intestine caused by a helminth co-infection would influence oral prion disease pathogenesis. When mice were co-infected with prions on d 8 after H. polygyrus infection the early accumulation of prions within Peyer's patches was reduced and survival times significantly extended. Natural prion susceptible hosts such as sheep, deer and cattle are regularly exposed to gastrointestinal helminth parasites. Our data suggest that co-infections with small intestine-restricted helminth pathogens may be important factors that influence oral prion disease pathogenesis.