Neuroinvasion of the enteric nervous system by prions is an important step in dissemination to the brain, yet very little is known about the basic process of enteric neuroinvasion. Using an alimentary model of neonatal disease transmission, neuroinvasion by scrapie prions in the ileum of lambs was detected by immunohistochemical staining for the disease-associated form of the prion protein, PrP Sc . Odds ratios (OR) were determined for the frequency of PrP Sc staining within enteric somata categorized by plexus location (myenteric, submucosal) and neurochemical staining (PGP 9.5, neural nitric oxide synthase, somatostatin, substance P, and vasoactive intestinal polypeptide). PrP Sc was observed in 4.48 § 4.26% of myenteric neurons and 2.57 § 1.82% of submucosal neurons in Wve lambs aged 208-226 days but not in a lamb aged 138 days. The relative frequency of PrP Sc within enteric somata was interdependent on plexus location and neurochemical type. Interestingly, PrP Sc was observed more frequently within myenteric neurons than in submucosal neurons (PGP 9.5; OR = 1.72, 95% conWdence interval = 1.21-2.44), and was observed within the myenteric plexus approximately 4£ (2.16-6.94) more frequently in somatostatin neurons than in the general neural population stained by PGP 9.5. Nerve Wbers stained for somatostatin were present in the mucosa and near PrP Sc staining within Peyer's patches. The results suggest that somatostatin-expressing enteric neurons, with Wber projections near Peyer's patches, but with somata present in greatest proportion within the myenteric plexus, are an early target for neuroinvasion by scrapie prions and could serve an important role in neural dissemination.