Knowledge regarding the clinical characteristics and natural history of acute infectious mononucleosis is based largely on older, often retrospective, studies without systematic follow-up. Differences in diagnosis, methodology, or treatment between historical and current practice might affect an understanding of this illness.

Using a prospective case series design, we enrolled 150 persons with an acute illness serologically confirmed as Epstein-Barr virus infection. The goal of the study was to assess symptoms, physical examination findings, laboratory tests, and functional status measures during the acute presentation and 1, 2, and 6 months later.

Acutely, infectious mononucleosis was characterized by the symptoms of sore throat and fatigue and substantial functional impairment. Objective physical and laboratory examination findings included pharyngitis and cervical lymphadenopathy, a moderate absolute and atypical lymphocytosis, and mildly elevated transaminase levels. The traditional signs of fever and splenomegaly were relatively uncommon. By 1 month, most symptoms and signs and all laboratory tests had returned to normal. Fatigue, cervical lymphadenopathy, pharyngitis, and functional health status improved more slowly.

In contemporary practice most of the classical illness features of infectious mononucleosis are observed. Symptoms, signs, and poor functioning might be protracted in some patients.