Forest fragmentation can influence abiotic and biotic factors important for the reproduction and survival of animals. Previous investigations suggest that, in the fall, more food is available for white-footed mice (Peromyscus leucopus) in edge than interior habitats and in small than large forest fragments. However, in the winter, individuals in small fragments and edge habitat may be more exposed to harsh weather extremes, which can result in higher mortality. We examined the effects of fragment size (small and large) and habitat (edge and interior) on populations of white-footed mice during nest box censuses in the winter (January–April) of 2003 in southwestern Ohio. While population density was initially higher in small than large fragments and edge than interior habitats, by the end of the winter there were no significant differences in population size. Populations in small fragments and edge habitat had larger decreases and greater rates of decline in density than those in large fragments and interior habitats over the course of the winter. These results suggest that while small fragments and edge habitat may be high quality habitat in the fall, animals in these areas may suffer higher mortality rates during the winter, compared with animals in large fragments and interior habitat.