Foscarnet is a pyrophosphate analogue that possesses substantial activity against human cytomegalovirus (HCMV) in patients with CMV retinitis. In this in vitro study we tested whether liposome encapsulation of foscarnet would provide the drug with anti-HCMV activity comparable with that of nonencapsulated foscarnet. The drug was entrapped in large unilamellar vesicles of homogeneous size at a concentration of 10 mg/ml. The vesicles were prepared by the method of fast and controlled dialysis of mixed detergent-lipid micelles using N-Octyl--D-glucopyranoside as the detergent. The activity of drugs against two laboratory HCMV strains (AD169 and Towne) was tested in a plaque-reduction assay using monolayers of human foreskin fibroblasts. The dose of encapsulated or nonencapsulated foscarnet required for a 50% reduction in the number of plaques (IC50) for the AD169 strain was 106 and 113 mumol/l, respectively. For the HCMV Towne strain the dose was 112 and 109 mumol/l, respectively. Treatment with concentrations of up to 400 mumol/l (maximal concentration tested) demonstrated that foscarnet is released at efficient doses from liposomes and that it is not toxic in the range of concentrations tested.