Sin Nombre virus (SNV) is an etiologic agent of hantavirus pulmonary syndrome. To better understand the natural history of this virus we studied population dynamics and temporal pattern of infection of its rodent hosts in southeastern Colorado (USA) from 1995 to 2000. We present evidence for the presence of two hantaviruses, SNV in deer mice (Peromyscus maniculatus) and El Moro Canyon virus in western harvest mice (Reithrodontomys megalotis), at our study sites. Sin Nombre virus appeared only sporadically in deer mouse populations; overall prevalence of antibody to SNV was 2.6%. El Moro Canyon virus was enzootic: seroconversions occurred throughout the year; antibody prevalence (11.9% overall) showed a delayed–density-dependent pattern, peaking as relative abundance of mice was declining. Males of both host species were more frequently infected than were females. An apparently lower mean survivorship (persistence at the trapping site) for SNV antibody-positive deer mice could indicate a detrimental effect of SNV on its host, but might also be explained by the fact that antibody-positive mice were older when first captured.