Sheep scrapie is a prion disease that requires interaction of exogenous prions with host prion protein (PrP) supporting prion formation. Disease is associated with deposition of a host-generated conformational variant of PrP, PrPsc, in a variety of tissues, including brain, resulting in fatal spongiform encephalopathy. Efficiency of PrPscformation is determined by polymorphisms in the PrP-coding sequence. This article adds to previous data of natural sheep scrapie, concentrating on the effect of host genotype and age on PrPscaccumulation patterns during preclinical and clinical disease. Two entire scrapie-infected, predominantly Suffolk-cross, sheep flocks euthanized for regulatory purposes were genotyped and analyzed for PrPscdeposition in various tissues using single- and dual-label immunohistochemistry. Scrapie, as defined by PrPscdeposition, occurred in 13/80 sheep. Preclinical disease was evident in nearly 70% of infected sheep, ranging in age from 14 months to 7 years. PrPscaccumulated systemically in the nervous tissue, various lymphoid tissues, both alimentary tract related and non–alimentary tract related, and the placenta. Clinical neurological illness was always associated with spongiform encephalopathy and PrPscdeposition in the brain. Only 6 of 9 sheep with preclinical scrapie had PrPscdeposition in the brain but widespread PrPscdeposition in peripheral lymphoid tissue, supporting previous data showing peripheral PrPscaccumulation preceding deposition in the brain. PrPsccolocalized with a marker for follicular dendritic cells throughout the lymphoid system. PrPscalso accumulated in the peripheral nervous system, particularly the nervous supply of the gastrointestinal tract. Abundant PrPscwas evident in trophoblast cells of placentomes but not in the endometrium, myometrium, or associated nervous plexus. PrPscdeposits were not observed in the mammary parenchyma or bone marrow. Scrapie susceptibility was defined genetically by PrP codon 171: PrPscdeposition was restricted to PrP genotype AA136RR154QQ171in 12/13 cases or AV136RR154QQ171in 1/13 cases. The earliest accumulation was observed in the single VRQ/ARQ heterozygous animal, consistent with the reported high scrapie susceptibility and brief incubation period observed in breeds with predominance of the V136R154Q171allele. Disease occurred within, as well as independent of, mother–daughter lines, suggesting both maternal and nonmaternal transmission in the flocks.