Probable transmission of bovine spongiform encephalopathy to humans has focused intense interest on all of the transmissible spongiform encephalopathies (TSEs) and how they spread. In all TSEs, an abnormal disease-associated, proteinase K-resistant protein referred to as PrP-res or PrPsc accumulates in brain. In some species, PrP-res accumulates in other tissues as well. Sheep placenta, brain, spleen, and lymph node were analyzed in detail for PrP-res and infectivity. Both were detected in all brain and spleen samples and in placenta and lymph nodes of 80% of the scrapie-infected sheep. A perfect correlation was observed between infectivity and PrP-res detection. These results substantiate the probability that placenta plays an important role in natural transmission of scrapie, suggest that analysis of placenta for PrP-res could be the basis for an antemortem test for sheep scrapie, and show that PrP-res, scrapie infectivity, and scrapie disease are closely associated.