Infectious mononucleosis is caused by Epstein-Barr virus (EBV), a member of the human herpesvirus family. A prodromal period of 3-5 days includes headache, malaise, myalgia, and fatigue. In adults, fever to 39°C (102.2°F) may persist for 7-10 days or longer in severe cases, with 80%-95% of people reporting some fever.

The classic clinical triad consists of fever, pharyngitis, and cervical adenopathy. Malaise, sweats, sore throat, anorexia, nausea, and headache are the most common symptoms. Myalgias, ocular muscle pain, chest pain, and rhinitis are not infrequent. Photophobia and arthralgias may also occur. The patient appears generally ill with readily apparent cervical adenopathy in most cases. Splenomegaly typically occurs during the second and third week. Hepatomegaly rarely develops.

The classic mononucleosis syndrome occurs almost without exception in teenagers and young adults.

Patients treated with ampicillin or penicillins often develop an exanthematous rash one week following initiation of therapy.

Splenic rupture, which is rare, may be fatal. Other rare complications include upper airway obstruction, hemolytic anemia, thrombocytopenic purpura, severe granulocytopenia, pneumonia, meningoencephalitis, recurrent aseptic meningitis (Mollaret's meningitis), Guillain-Barré syndrome, Miller Fisher syndrome (bilateral ptosis, total ophthalmoplegia, cerebellar symptoms and hyporeflexia), psychosis, Bell palsy, myocarditis, pericarditis, coronary artery spasm, pancreatitis, nephritis, and fulminating hepatic necrosis. Neurological complications, airway obstruction, and splenic rupture are the most common causes of death in otherwise healthy persons. Gastrointestinal symptoms, palatal petechiae, and insidious onset are associated with a prolonged recovery period. Occasionally, jaundice, arthritis, and pneumonitis are seen.