During a 50-month period the diagnosis of heterophil antibody negative infectious mononucleosis or of a mononucleosis-like illness was made in 43 patients with a variable clinical picture and significant numbers of atypical lymphocytes. Epstein-Barr virus (EBV)-related serologic tests revealed that seven patients had primary EBV infections based on the detection of immunoglobulin M (IgM) antibodies to EB-viral capsid antigens (IgM-VCA) and the absence of anti-Epstein-Barr virus associated nuclear antigen (EBNA) on most initial specimens (six of seven cases). Thirty cases were due to active cytomegalovirus (CMV) infections and both detectable CMV-macroglobulins (≧1:32) and significant anti-CMV titers were present by a complement fixation technic. Abnormalities in liver function were less marked in CMV than in EBV infections in age-matched subjects. Of the remaining six cases, one was due to rubella and one to toxoplasmosis. Four cases were of undetermined etiology. Serums from 38.1 per cent of the patients with heterophil-antibody positive infectious mononucleosis were found to "cross react" in the IgM-CMV test, but serums from patients with acute CMV infection did not cross react in the VCA-specific IgM test. In nine of 36 cases without heterophil antibody (six due to CMV, one due to toxoplasmosis and one apparent infectious hepatitis), anti-D or -R of the early-antigen (EA) complex was detected (1:10 to 1:40), raising the question of reactivation of the EBV-carrier state by intervening infections mainly of viral origin.