SUMMARY Six calves were inoculated with 1 of 2 North American serotypes of epizootic hemorrhagic disease virus (ehdv) and then inoculated with the second serotype 16 weeks later. One calf did not develop an immune response to ehdv after primary inoculation and was removed from the study. Viremia after primary inoculation was transient. Although each infected calf developed a high serum neutralizing antibody titer to ehdv, at no time after inoculation with one or both viruses was antibody detected that neutralized any US serotypes of bluetongue virus. After exposure to both serotypes of ehdv, 4 of 5 calves developed antibodies that cross-reacted with group-specific bluetongue virus antigens.