Technical Abstract: Scrapie, a transmissible spongiform encephalopathy (TSE), is a naturally occurring fatal neurodegenerative disease of sheep and goats. This study documents incubation periods, pathological findings and distribution of abnormal prion proteins (PrP**Sc) by immunohistochemistry and Western blot in tissues of genetically susceptible and resistant neonatal lambs inoculated with a pool of U.S. sheep scrapie material. Nine Suffolk lambs with genotypes AA/RR/QQ (n = 5) and AA/RR/QR (n = 4) at codons 136, 154, and 171, respectively) were orally inoculated within 12 hours of birth with 1 ml of a 10% brain suspension consisting of a pool of scrapie-affected sheep brains. Inoculated animals were euthanized when advanced clinical signs of scrapie were observed. All AA/RR/QQ sheep developed clinical signs of scrapie with a mean survival time of 24 months. Spongiform lesions in the brains and PrP**Sc deposits in central nervous system (CNS) and lymphoid tissues were present in these sheep. None of the QR sheep succumbed to the disease. A previous study using a larger volume (30 ml of 10% brain suspension) of the same inoculum in four-month-old Suffolk lambs documented longer survival periods (average 32 months) and only 5 of 9 inoculated sheep developed scrapie. This study demonstrates that neonatal QQ lambs have increased susceptibility to scrapie compared to older animals and that a smaller dose of inoculum (i.e. 1/30th the volume) induces a higher attack rate when compared to lambs inoculated at four months of age using the same inoculum.