An epidemiologic case-control study was conducted to identify factors that predispose Peromyscus spp. to the risk of infection with Giardia sp. in watersheds. A total of 200 Giardia sp.–positive mice (cases) and a similar number of Giardia sp.–negative mice (controls) were selected from a population 2,528 mice captured in a watershed in southeastern New York State. The Giardia sp. infection status of the mice was determined by centrifugation concentration flotation and an enzyme-linked immunosorbent assay. The mice were later classified into 2 species, Peromyscus maniculatus and P. leucopus, using cellulose acetate electrophoresis of individual saliva samples. The risk of infection was evaluated while controlling for indigenous factors (age and sex) and exogenous factors (habitat and land use) that were hypothesized to influence the likelihood of infection with Giardia sp. The study population consisted of 257 (59%) P. leucopus and 165 (41%) P. maniculatus. Peromyscus leucopus mice were at a higher risk of becoming infected with Giardia in comparison to P. maniculatus (adjusted odds ratio = 40). The risk of Giardia sp. infection varied with the age of the animals, since adult animals were at higher risk than juvenile animals. This study suggested a difference in susceptibility to Giardia sp. between different species of mice.