Prairie dogs are notoriously difficult to enumerate, with previously methods including visual counts, mark-resight, burrow counts, and catch per unit effort. Unlike those methods, spatial capture-recapture (SCR) analyses allow for formal estimation of density along with associated estimates of uncertainty, detection probability, and the size of the average area over which an individual was detected during the study period (referred to as an activity center). Using SCR analyses, we compared density estimates as part of a field trial evaluating the effectiveness of an oral sylvatic plague vaccine in black-tailed prairie dogs (Cynomys ludovicianus), Gunnison's prairie dogs (C. gunnisoni), white-tailed prairie dogs (C. leucurus), and Utah prairie dogs (C. parvidens) at 11 study areas in the western United States. The study was designed as a matched pairs analysis that included 27 individual paired plots (54 plots), each consisting of a plot treated with vaccine baits and a plot treated with placebo baits. Overall, we captured >3,000 individuals each year on these plots, and recapture rates ranged from 5–87%. For black-tailed prairie dogs, density estimates ranged from 2.7 individuals/ha (95% CI = 2.2–3.3/ha) to 77.3/ha (63.2–94.4/ha), and for Gunnison's prairie dogs, estimates ranged from 11.7/ha (10.6–12.8/ha) to 15.4/ha (14.4–16.7/ha). White-tailed prairie dogs were at their lowest density (3.3/ha, 95% CI = 2.9–3.8/ha) during the first year of the study and their highest density (14.5/ha; 13.5–15.6/ha) during the last year of the study. Utah prairie dog density estimates ranged from a low of 4.0/ha (95% CI = 3.55–4.6/ha) to a high of 20.8/ha (16.8–25.8/ha). Best-fitting models of prairie dog density indicated increasing patterns of density over time on most study plots, negative effects of plague, and positive effects of vaccination. Finally, we found low correlations between catch per unit effort estimates from previous published literature at these sites and our densities estimates. Spatial capture-recapture estimates allowed us to consistently compare treatment effects across space and time, although some exceptions are noted where we observed significant movement between plots within a pair (3 pairs) and when trapping effort between plots or years was not consistent.