This study examined environmental and physiological mediators of responses to hantavirus in wild-caught Norway rats. Rats were trapped in Baltimore, Maryland from 1996 to 2000, and prevalence of Seoul virus in target tissues, antibody responses against Seoul virus, concentrations of steroid hormones, and masses of reproductive organs were measured. Approximately 50% of live-trapped rats were infected with Seoul virus. No seasonal or photoperiodic changes in prevalence of Seoul virus infection or in antibody responses against Seoul virus were observed. Animals trapped during low temperatures had higher antibody responses than animals trapped during mild temperatures. Adults were more likely to have Seoul virus in kidneys and lungs and have higher antibody responses than juveniles. Older adult rats also were more likely to be infected and have higher antibody responses than younger adults. Rates of Seoul virus infection were similar between sexes; females, however, had higher anti–Seoul virus IgG responses than males. Although age- and season-related changes in concentrations of steroid hormones were observed, concentrations were not related to variation in infection by Seoul virus. Finally, the masses of reproductive organs increased with age, were responsive to environmental changes, and may be related to variation in Seoul virus infection. Thus, physiological and behavioral changes associated with sexual maturation may be the best predictors of Seoul virus infection in Norway rats, suggesting that metabolic trade-offs among growth, reproduction, and immune function occur at the onset of puberty.