Prion diseases are neurodegenerative diseases characterized by the accumulation of misfolded prion protein (PrP^Sc) in the brain and other tissues. Animal prion diseases include scrapie in sheep, chronic wasting disease (CWD) in cervids, and transmissible mink encephalopathy (TME) in ranch-raised mink. We investigated the susceptibility of raccoons to various prion disease agents and compared the clinicopathologic features of the resulting disease. Raccoon kits were inoculated intracranially with the agents of raccoon-passaged TME (TME^Rac), bovine-passaged TME (TME^Bov), hamster-adapted drowsy (TME^DY) or hyper TME (TME^HY), CWD from white-tailed deer (CWD^Wtd) or elk (CWD^Elk), or atypical (Nor98) scrapie. Raccoons were euthanized when they developed clinical signs of prion disease or at study endpoint (<82 mo post-inoculation). Brain was examined for the presence of spongiform change, and disease-associated PrP^Sc was detected using an enzyme immunoassay, western blot, and immunohistochemistry. All raccoons inoculated with the agents of TME^Rac and TME^Bov developed clinical disease at ~6.6 mo post-inoculation, with widespread PrP^Sc accumulation in central nervous system tissues. PrP^Sc was detected in the brain of 1 of 4 raccoons in each of the CWD^Wtd-, CWD^Elk-, and TME^HY-inoculated groups. None of the raccoons inoculated with TME^DY or atypical scrapie agents developed clinical disease or detectable PrP^Sc accumulation. Our results indicate that raccoons are highly susceptible to infection with raccoon- and bovine-passaged TME agents, whereas CWD isolates from white-tailed deer or elk and hamster-adapted TME^HY transmit poorly. Raccoons appear to be resistant to infection with hamster-adapted TME^DY and atypical scrapie agents.