Of 9 New Zealand White rabbits inoculated at multiple sc and im sites with a single dose of Herpesvirus saimiri (HVS), 2 developed malignant lymphomas 40-50 days post inoculation. At least 1 animal developed a terminal leukemic phase of the disease. HVS was isolated from the oral and conjunctival swabs and blood and tissue lymphocytes, but not from monolayer cell cultures derived from kidney or lung tissues of the diseased animals. The inoculated rabbits developed low titers of neutralizing antibodies against the virus. Antibodies against HVS specific early and late antigens were not detected in the sera of 7 animals that failed to develop clinical disease, but were detected in the serum of the 1 rabbit with lymphoma. The immunologic response of rabbits to HVS infection was compared to similar responses in infected nonhuman primates.