The antiviral effects of humoral antibodies and adenine arabinoside on encephalitis due to Herpesvirus hominis were studied in three-week-old mice. Exogenously administered antibodies to H. hominis, of rabbit or human origin, significantly reduced morbidity and mortality rates from H. hominis encephalitis if enough antibodies were given during the early phase of infection. Adenine arabinoside could also modulate the pathogenesis and reduce the mortality rate in mice with H. hominis encephalitis. Simultaneous administration of adenine arabinoside and human immune globulin resulted in an enhanced protection against H. hominis encephalitis. This increased protection was manifested by a significant reduction of mortality rate, a decrease in concentration of virus, and a lessening of histopathologic damage in the brain tissues. Mechanisms involved in the enhanced protective effects were not well defined. The use of adenine arabinoside plus human immune globulin did not completely suppress viral replication. Therefore, host recovery was probably mediated through (1) partial suppression of viral replication by adenine arabinoside, (2) neutralization of cell-free virus by antibodies, and (3) collaboration of antibodies with other host resistance factors (e.g., complement, leukocytes, nonimmune effector cells, etc.). Our data suggest that control of severe H. hominis infection may require the combined use of an antiviral agent and humoral factor and, perhaps, enhancement of host responses by other means.