Technical Abstract: Transmissible Mink Encephalopathy (TME) occurs as sporadic outbreaks associated with ingestion of feed presumably contaminated with some type of prion disease. Mink lack a species barrier to primary oral challenge with Bovine Spongiform Encephalopathy, whereas they have a barrier to such challenge with Scrapie. We investigated whether mink have a species barrier to chronic wasting disease (CWD) by performing primary intracerebral (IC) and primary oral challenge with CWD positive elk brain. Primary IC challenge resulted in clinical disease in 2/8 mink at 31 to 33 months incubation. Affected mink had spongiform vacuolation, astrocytosis, and neurodegeneration within the central nervous system and immunoreactivity to disease associated prion protein (PrPd) in brain, retina and lymph node. CWD IC recipients had significantly lower brain vacuolation and PrPd deposition scores, significantly lower cerebrocortical astrocyte counts and significantly higher hippocampal astrocyte counts, than TME IC recipients. Primary oral challenge with CWD positive elk brain (n=22), or CWD negative elk brain given IC (n=7) or orally (n=23), did not result in clinical or microscopic abnormalities during 42 months observation. Novel prion gene polymorphisms were identified at codon 27 (arginine/tryptophan) and codon 232 (arginine/lysine). This study shows that, while CWD can cause disease when given IC to mink, the lesions are not characteristic of TME, it is inefficient compared to TME, and oral challenge does not result in disease. The demonstration of a species barrier in cervid to mustelid prion transmission indicates mink are unlikely to be involved in natural CWD transmission.