CMX001, an orally active lipid conjugate of cidofovir (CDV), is 50 times more active in vitro against herpes simplex virus (HSV) replication than acyclovir (ACV) or CDV. These studies compared the efficacy of CMX001 to ACV in BALB/c mice inoculated intranasally with HSV types 1 or 2. CMX001 was effective in reducing mortality using doses of 5 to 1.25 mg/kg administered orally once daily even when treatments were delayed 48-72 h post viral inoculation. Organ samples from mice treated with CMX001 had titers three to five log10 pfu/gram of tissue lower than samples from ACV treated mice, including five different regions of the brain. Detectable concentrations of drug-related radioactivity were documented in the central nervous system of mice following oral administration of 14C-CMX001. These studies indicated that CMX001 penetrates the blood brain barrier, is a potent inhibitor of HSV replication in disseminated and CNS infections and is superior to ACV.