Scrapie is the transmissible spongiform encephalopathy (TSE) of sheep and goats, and ovine scrapie eradication is based in part on strong genetic resistance to classical scrapie. Goats may serve as a scrapie reservoir, and to date there has been no experimental confirmation of strong genetic resistance in goats. Two prion protein variants (amino acid substitutions S146 and K222) in goats have been significantly underrepresented in scrapie cases though present in exposed flocks, and have demonstrated low cell-free protein conversion efficiency to the disease form (PrPD). To test degree of genetic resistance conferred in live animals with consistent exposure, we performed the first experimental challenge of goats singly heterozygous for either PRNP S146 or K222. We used a naturally-infected goat brain/placentome homogenate as oral inoculum during the first 24 hours after birth to achieve maximal uptake. All N146-Q222 homozygotes became clinically scrapie positive by an average of 24 months, but all S146 and K222 heterozygotes remain scrapie negative by both rectal biopsy and clinical signs at significantly longer incubation times (P<=0.0001). Recent reports indicate small numbers of S146 and K222 heterozygous goats have become naturally infected, suggesting these alleles do not confer complete resistance in the heterozygous state but rather extended incubation. At an average of almost 42 months and counting (almost 18 months average extended incubation to date), the K222 heterozygote group already demonstrates the longest extended incubation in experimental scrapie challenged goats of which we are aware. This study is ongoing to determine the full length of extended incubation.