Hantavirus activity in 39 National Parks in the eastern and central United States was surveyed by testing 1,815 small mammals of 38 species for antibody reactive to Sin Nombre virus. Antibody-positive rodents were found throughout the area sampled, and in most biotic communities. Antibody was detected in 7% of 647 deer mice (Peromyscus maniculatus), 2% of 590 white-footed mice (P. leucopus), 17% of 12 rice rats (Oryzomys palustris), 3% of 31 cotton rats (Sigmodon hispidus), and 33% of 18 western harvest mice (Reithrodontomys megalotis). Antibody was also found in three of six species of voles, and in one of 33 chipmunks (Tamias minimus). Prevalence among Peromyscus was highest in the northeast. Although few cases of hantavirus pulmonary syndrome have been identified from the eastern and central regions, widespread infection in reservoir populations indicates that potential exists for human infection throughout much of the United States.