Control of mid-sized mammalian predators (hereafter, mesopredators) is sometimes advocated in an attempt to reduce their impact on wildlife populations, particularly economically important (i.e., game) or endangered species. However, mesopredators may play a role in regulating small mammal populations; thus, lethal control of mesopredators may have unintended consequences. The hispid cotton rat (Sigmodon hispidus; hereafter, cotton rat) is one of the most common small mammals in the southeastern United States and is an important prey species for several of the region's predators. Within fire-maintained communities, such as the longleaf pine (Pinus palustris) forests of the Coastal Plain, cotton rat populations dramatically, yet temporarily, decline following prescribed fire. To evaluate the effects of mesopredator removal on cotton rat survival and cause-specific mortality, we conducted a large-scale mesopredator exclusion experiment that incorporated a prescribed fire during the winter of study. Between 18 May 2006 and 20 June 2007, we used radio-telemetry to monitor 252 cotton rats (131 in exclosures and 121 in controls) and documented 184 mortalities. During the 37-week period of monitoring prior to the prescribed fire event, weekly survival of cotton rats was greater in mesopredator exclusion plots. During the 19 weeks following the prescribed fire, there were no differences in weekly survival relative to mesopredator treatment, but fire caused a short-term reduction in weekly survival within both exclosures and controls. Of 36 cotton rats monitored on the date of prescribed fire, 18 were depredated within 1 month, 4 emigrated, and 5 were killed by the fire event. Overall, raptors preyed on cotton rats more in exclosures than in controls, but evidence for compensatory predation (raptor-caused morality greater in exclosures than in controls although survival rates were similar between treatments) only occurred following the prescribed fire event. Our results suggest that managing mesopredators may result in a temporary increase in cotton rat survival, but dormant season prescribed fire removes this effect until well into the following growing season.