Fifty-six patients with a clinical and laboratory diagnosis of infectious mononucleosis who had not been ill for more than seven days, were randomised for peroral treatment with acyclovir (800 mg five times daily) or placebo for seven days in a double blind trial. Clinical, virological and immunological parameters were monitored in each patient for six months. During treatment, shedding of Epstein-Barr virus' as assessed in 36 patients, was significantly reduced (p less than 0.001). However, virus production in the oropharynx returned to pre-treatment levels one week after the cessation of therapy. Virus was detected in 35 patients at enrollment and in 28 of 36 patients at the six-month control. No effect on the clinical course of the disease was noticed. The virus-specific antibody response was also unaffected. A significant reduction in spontaneous outgrowth of in vivo Epstein-Barr virus-infected B-lymphocytes was found at 180 days after treatment in four acyclovir-treated patients compared to six controls (p less than 0.001). In another three patients with over-whelming clinical symptoms causing airway obstruction and/or disseminated intravascular coagulopathy, treatment with intravenous acyclovir (10 mg/kg three times daily) was combined with prednisolone (0.7 mg/kg daily) for ten days. Virus shedding ceased transiently during treatment, but returned to initial levels within one week. A dramatic clinical effect on the pharyngeal oedema and general health of the two patients with airway obstruction was noticed, but was much less evident in a patient with intravascular coagulopathy.