Transmission of sheep scrapie and some other prion diseases, including variant Creutzfeldt-Jakob disease of man, probably occurs via the oral route. A disease-associated variant of the host-coded prion protein (PrP(d)) accumulates in germinal center follicles of lymphoid tissues, including Peyer's patches of the gut, where it can be detected before its accumulation in the central nervous system. To investigate the potential role of lymphoid tissue nerves in neuroinvasion, we used immunohistochemical methods to study the frequency and distribution of nerves and PrP(d) accumulation in Peyer's patches and other lymphoid tissues from scrapie-affected and unaffected sheep. Nerves were infrequently found in secondary follicles of Peyer's patches, but never in germinal centers of the other lymphoid tissues tested. No differences in the frequency or distribution of nerves were found in relation to the presence or absence of PrP(d) accumulation. PrP(d) accumulation and nerves were only infrequently present together in Peyer's patches. These results suggest that, even if amplification of infectivity in lymphoid tissues facilitates neuroinvasion, nerves within lymph nodes and germinal centers of Peyer's patches do not play a primary role in transport of infectivity to the central nervous system. However, sheep between 2 and 4 months of age had significantly more nerve fibers within follicles than older groups. It is therefore possible that a general increase in nerve density of the intestine during early phases of life may contribute to an increased susceptibility of young animals to oral prion infection.