Prion diseases are associated with the accumulation of an abnormal form of the host-coded prion protein (PrP). It is postulated that different tertiary or quaternary structures of infectious PrP provide the information necessary to code for strain properties. We show here that different light microscopic types of abnormal PrP (PrP(d)) accumulation found in each of 10 sheep scrapie cases correspond ultrastructurally with abnormal endocytosis, increased endo-lysosomes, microfolding of plasma membranes, extracellular PrP(d) release and intercellular PrP(d) transfer of neurons and/or glia. The same accumulation patterns of PrP(d) and associated subcellular lesions were present in each of two scrapie strains present, but they were present in different proportions. The observations suggest that different trafficking pathways of PrP(d) are influenced by strain and cell type and that a single prion strain causes several PrP(d)-protein interactions at the cell membrane. These results imply that strains may contain or result in production of multiple isoforms of PrP(d).