Gunnison’s prairie dogs (Cynomys gunnisoni) have been considered at greater risk from Yersinia pestis (plague) infection in the montane portion of their range compared to populations at lower elevations, possibly due to factors related to flea transmission of the bacteria or greater host susceptibility. To test the latter hypothesis and determine whether vaccination against plague with an oral sylvatic plague vaccine (SPV) improved survival, we captured prairie dogs from a C. g. gunnisoni or “montane” population and a C. g. zuniensis or “prairie” population for vaccine efficacy and challenge studies. No differences (P = 0.63) were found in plague susceptibility in non-vaccinated animals between these two populations; however, vaccinates from the prairie population survived plague challenge at significantly higher rates (P < 0.01) than those from the montane population. Upon further analysis, we determined that response to immunization was most likely associated with differences in age, as the prairie group was much younger on average than the montane group. Vaccinates that were juveniles or young adults survived plague challenge at a much higher rate than adults (P < 0.01 and P = 0.02, respectively), but no difference (P = 0.83) was detected in survival rates between control animals of different ages. These results suggest that host susceptibility is probably not related to the assumed greater risk from plague in the C. g. gunnisoni or “montane” populations of Gunnison’s prairie dogs, and that SPV could be a useful plague management tool for this species, particularly if targeted at younger cohorts.