The plague bacterium Yersinia pestis is lethal to endangered black-footed ferrets (Mustela nigripes, BFF) and the prairie dogs (Cynomys spp., PD) on which they depend for habitat and prey. We assessed the effectiveness of an oral sylvatic plague vaccine delivered in baits to black-tailed PD (Cynomys ludovicianus, BTPD) from 2013 to 2017 on the Charles M. Russell National Wildlife Refuge (CMR) in northcentral Montana. We permanently marked BTPD on four paired vaccine (N = 1,349 individuals) and placebo plots (N = 926; 7,027 total captures). We analyzed capture–recapture data under a Cormack–Jolly–Seber model to estimate annual apparent survival. Overall, survival averaged 0.05 lower on vaccine plots than on paired placebo plots. Immediately before noticeable die-offs and detecting plague on pairs CMR1 and CMR2, 89% of BTPD sampled on vaccine plots had consumed at least one bait and the immune systems (pleural) of 40% were likely boosted by consuming baits over multiple years. Survival to the following year was 0.16 and 0.05 on the vaccine plots and 0.19 and 0.06 on the placebo plots for pairs CMR1 and CMR2, respectively. These rates were markedly lower than 0.63, the overall average estimate on those same plots during the previous 3 years. PD populations subjected to such large die-offs would not be expected to sustain a BFF population. An overriding limitation to achieving sufficient protection rests with vaccine delivery constraints. Late summer/fall bait distribution results in the highest bait uptake rates. However, the PD birth pulse each spring can double the size of populations in most years, greatly reducing the proportion of vaccinates in populations and diminishing potential herd immunity benefits. In addition to nonvaccinated juveniles and PD that do not consume bait, incomplete vaccine protection and time required for immunity to develop leaves a large majority of PD populations vulnerable to plague for 6–7 months or more each year.