Pharmacological induction of low deoxyribonucleoside triphosphate (dNTP) levels is a novel approach to combine inhibition of virus replication. In accordance with this concept, the alteration of antiherpes activity of cytarabine (AraC) in combination with hydroxyurea (HU), an inhibitor of ribonucleotide reductase, was studied. The results were confirmed by virus yield assays in human embryonic skin-muscle fibroblasts (HESMF). It was demonstrated that HU significantly enhanced the antiviral activity of AraC against HSV-1 and HSV-2 in HESMF cultures and this inhibition was reversed by an excess of deoxycytidine (dCyt). The observations suggest that the reduction in dCTP level accounts for the potentiating effect of HU on the antiviral activity of AraC.