Infection with human cytomegalovirus (HCMV) can cause serious complications in bone-marrow and solidorgan transplant recipients, and current therapies are not optimal. We evaluated 2 orally active ether lipid ester analogues of cidofovir (CDV)—hexadecyloxypropyl-CDV (HDP-CDV) and octadecyloxyethyl-CVD(ODECDV)—in severe combined immunodeficient mice in which either human fetal retinal tissue or human fetal thymus and liver tissue had been implanted and was later infected with HCMV. Our results indicate that orally administered treatment with either HDP-CDV or ODE-CDV is 4-8-fold more active, on a molar basis, than is intraperitoneally administered CDV. These data suggest that HDP-CDV and ODE-CDV should be further evaluated as potential antiviral agents for treatment of HCMV infection.