Acyclovir (ACV) has an ED50 of 0.3 microM against EBV replication in vitro. Based on these and other data we carried out a pilot, double-blind, placebo-controlled trial of ACV for treatment of infectious mononucleosis. Only patients with relatively severe illness requiring hospital management were enrolled. Ten subjects with proven infectious mononucleosis received placebo and 10 ACV. The drug was administered intravenously at 8-hourly intervals in a total daily dosage of 1500 mg/m2 for 5 days. Preliminary analyses of the results indicate that the drug interrupted virus excretion in the oropharynx transiently but had no effect on ability to generate lymphocytic lines from peripheral blood. Symptoms and signs unaffected by ACV were splenomegaly, lymphadenopathy, lethargy, fever and pharyngitis. There was significantly more rapid regain of weight in the ACV-treated group. On the basis of these results we have instituted an out-patient trial of orally administered ACV in patients with less severe illness earlier in its course. We have also begun in-vitro tests of other drugs that might prove to be effective against Epstein-Barr virus infection, and have shown that 9-1 (1,3-dihydroxy-2-propoxymethyl)guanine (BW759) has an ED50 of 0.05 microM.