The effects of different antiviral drug combinations on the replication of various human cytomegalovirus (CMV) strains in human embryonic lung (HEL) fibroblasts were evaluated. HPMPC combined with either ganciclovir, foscarnet or acyclovir showed additive to synergistic inhibition of CMV replication. Combinations of zidovudine with HPMPC, ganciclovir, foscarnet or acyclovir also resulted in additive to synergistic inhibition of CMV replication. Synergism tended to be higher for the clinical CMV isolates than for the reference strains AD-169 and Davis. Suppression of CMV replication was obtained at lower drug concentrations when the drugs were combined than when the drugs were used alone. At the highest drug concentrations used in the antiviral activity experiments, neither drug alone nor its combination suppressed host cell growth. If higher drug concentrations were used, zidovudine increased the inhibitory effects of ganciclovir, acyclovir and foscarnet but not of HPMPC, on cell proliferation. Use of combinations in the therapy of CMV infections may be considered to enhance drug efficacy, to reduce toxicity and, possibly, to diminish the risk of emergence of drug-resistant virus strains.