Four atypical cases of presumed infectious mononucleosis (IM) encephalitis are presented. To establish an etiologic diagnosis, Paul-Bunnell-Davidsohn heterophil titers (PBD), antibody titers to the antigens of the Epstein-Barr virus (EBV), and oropharyngeal excretion of EBV were determined. Criteria for a primary EBV infection are (1) an antiviral capsid antigen titer of 1:160 or greater, (2) the presence of antibody to the diffuse component of the early antigen, (3) absence of antibody to the nuclear antigen, and (4) excretion of the virus from the oropharynx. Three of the four cases met these criteria; of the three, one did not have a positive heterophil titer. The fourth case turned out not to be IM; there was a positive PBD heterophil, but there was no evidence of primary EBV infection. Although the PBD heterophil is usually a reliable test to diagnosis IM, it is not always present in children, and it is sometimes nonspecifically elevated. Some EBV titers can be nonspecifically elevated as well; however, the above criteria are diagnostic of primary EBV infection.