A better understanding of the infectious process in scrapie was sought by studying the temporal distribution of virus in naturally infected Suffolk sheep. Virus was detected (by mouse inoculation) first in lymphatic tissues and intestine of clinically normal lambs (age, 10–14 months). Titers were generally low. Infection of the central nervous system was first detected in a 25-month-old clinically normal sheep whose nonneural tissues had moderate amounts of virus. In sheep affected with scrapie, similar amounts in nonneural tissues accompanied high concentrations in the central nervous system, notably in sites of severest neurohistologic changes. No virus was found in clinically normal high-risk sheep 54 to 104 months old. The early appearance of virus in tonsil, retropharyngeal and mesenteric-portal lymph nodes, and intestine suggests that primary infection occurs by way of the alimentary tract, either prenatally from virus in amniotic fluid or postnatally from virus in a contaminated environment.