Differences in innate disease resistance at the sub-species level have major implications for wildlife management. Two subspecies of white-tailed deer, Odocoileus virginianus borealis and O. virginianus texanus were infected with epizootic hemorrhagic disease (EHD) viruses. These viruses are highly virulent pathogens of white-tailed deer and are endemic within the range of O. virginianus texanus but not within the range of O. virginianus borealis. Two experimental infections were performed. Five O. virginianus texanus fawns and five O. virginianus borealis fawns were infected with 10(7.1) median tissue culture infective doses (TCID50) of EHD virus, serotype 1 and five of each subspecies were infected with 10(7.1) TCID50 of EHD virus, serotype 2. Infections with both EHD virus serotypes caused severe clinical disease and mortality in O. virginianus borealis fawns, whereas disease was mild or nondetectable in O. virginianus texanus fawns. Virus titers and humoral immune response were similar in both subspecies suggesting that differences in innate disease resistance explain the differences seen in clinical disease severity. In white-tailed deer, innate disease resistance may vary at the subspecies level. Should this phenomenon occur in other species, these findings have major implications for managing wildlife populations, both endangered and non-endangered, using tools such as translocation and captive propagation.