Experimental infection with Herpesvirus sylvilagus produces clinical and histopathologic changes in its natural host, the cottontail rabbit (Sylvilagus floridanus), similar to those observed in humans acutely infected with Epstein-Barr virus (EBV). Twenty-seven seronegative cottontail rabbits were infected with Herpesvirus sylvilagus and all developed antibodies within 10 days. Neutralizing antibody was detected as early as 7 days after infection. Virus was isolated from blood mononuclear cells, spleen, bone marrow, thymus, lymph nodes, kidneys, lung, and liver as early as 3 days after infection. Infected animals showed leucocytosis, monocytosis, and lymphocytosis with the appearance of atypical lymphocytes. Peripheral blood abnormalities peaked at 10-14 days after infection, and returned to normal by 28 days after infection, with the exception of atypical lymphocytosis that persisted in some animals for more than 2 years after experimental infection. More severe histopathologic changes were seen in virus-infected juvenile rabbits than adult rabbits; these changes included viral myocarditis, interstitial pneumonia, and lymphocytic myositis. Reactive hyperplasia and subsequent lymphocytic depletion of spleen and lymph nodes were reminiscent of that seen in virus-associated hemophagocytosis syndrome. Prominent lymphoid hyperplasia of many nonlymphoid organs, most notably the kidney and lungs, was observed. The development of these lymphoproliferative lesions and other lymphoid changes during H. sylvilagus infection suggest that this system may be a model to study similar lesions induced by EBV infection in humans.