Laboratory trials conducted over the past decade at USGS National Wildlife Health Center indicate that wild populations of prairie dogs (Cynomys spp.) display different degrees of susceptibility to challenge with fully virulent Yersinia pestis, the causative agent of plague. We evaluated patterns in prairie dog susceptibility to plague to determine if the historical occurrence of plague at location of capture was related to survival times of prairie dogs challenged with Y. pestis. We found that black-tailed prairie dogs from South Dakota (captured prior to the detection of plague in the state), Gunnison's prairie dogs from Colorado, and Utah prairie dogs from Utah were most susceptible to plague. Though the susceptibility of black-tailed prairie dogs in South Dakota compared to western locations supports our hypothesis regarding historical exposure, both Colorado and Utah prairie dogs have a long history of exposure to plague. It is possible that for these populations, genetic isolation/bottle necks have made them more susceptible to plague outbreaks.