Sections of the medulla oblongata from the brains of sheep were examined for prion protein (PrP) by immunohistochemistry. On the basis of the morphology and neuroanatomical distribution of the deposits, distinct disease-associated patterns of PrP deposition were identified in scrapie-affected sheep, suggesting at least four distinct phenotypes of scrapie. In addition, clearly defined patterns of PrP deposition, readily distinguished from the disease-associated PrP deposits, were identified in some normal sheep from scrapie-free flocks. In five sheep, believed to be preclinically affected by scrapie, PrP deposition of a disease-specific type but of restricted distribution was identified, demonstrating the sensitivity of the technique for the diagnosis of scrapie. The neuroanatomical distribution of these early PrP deposits suggest that the route of entry of the scrapie agent into the brain is via parasympathetic motor neurons in the vagus nerve which innervate the gastrointestinal tract.