Viruses in the epizootic hemorrhagic disease (EHD) serogroup are the most frequent cause of hemorrhagic disease in the southeastern United States, but nothing is known about cross-protection between the two EHD serotypes (EHDV-1 and EHDV-2) present in this region. We experimentally tested whether deer surviving EHDV-2 infection would be protected against subsequent infection with EHDV-1, and used field data to examine the possibility of reciprocal cross-protection. Eleven white-tailed deer fawns (Odocoileus virginianus) were experimentally infected with EHDV-2 and later challenged with EHDV-1. Two EHDV-2-naïve fawns also were infected with EHDV-1. Deer were monitored via physical examination, complete blood counts, clotting profiles, viral isolation, and serology, and each animal was assigned a quantitative clinical disease severity score based on presence of certain physical and clinical parameters. Infection of naïve controls with EHDV-1 caused severe clinical disease and death of both fawns, whereas deer previously infected with EHDV-2 exhibited no or minimal signs of disease. Thus, infection with EHDV-2 conferred protection against disease caused by subsequent EHDV-1 infection. Although prior EHDV-2 exposure protected deer from severe clinical disease, it did not prevent infection nor viremia indicating they could still act as virus amplifying hosts. These experimental infections suggest that EHDV-1 and 2 may exist in a state of mutual permissiveness.