We confirmed safety and immunogenicity of mass-produced vaccine baits carrying an experimental, commercial-source plague vaccine (RCN-F1/V307) expressing Yersinia pestis V and F1 antigens. Forty-five juvenile black-tailed prairie dogs (Cynomys ludovicianus) were randomly divided into three treatment groups (n=15 animals/group). Animals in the first group received one standard-dose vaccine bait (5×10⁷ plaque-forming units [pfu]; STD). The second group received a lower-dose bait (1×10⁷ pfu; LOW). In the third group, five animals received two standard-dose baits and 10 were left untreated but in contact. Two vaccine-treated and one untreated prairie dogs died during the study, but laboratory analyses ruled out vaccine involvement. Overall, 17 of 33 (52%; 95% confidence interval for binomial proportion [bCI] 34−69%) prairie dogs receiving vaccine-laden bait showed a positive anti-V antibody response on at least one sampling occasion after bait consumption, and eight (24%; bCI 11–42%) showed sustained antibody responses. The STD and LOW groups did not differ (P≥0.78) in their proportions of overall or sustained antibody responses after vaccine bait consumption. Serum from one of the nine (11%; bCI 0.3–48%) surviving untreated, in-contact prairie dogs also had detectable antibody on one sampling occasion. We did not observe any adverse effects related to oral vaccination.