We studied the susceptibility of human herpesvirus 8 (HHV-8) to a number of antiherpesvirus agents. The acyclic nucleoside phosphonate (ANP) analogs cidofovir and HPMPA [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine] effected potent inhibition of HHV-8 DNA synthesis, with 50% effective concentrations (EC50) of 6.3 and 0.6 microM, respectively. Adefovir, an ANP with both antiretrovirus and antiherpesvirus activity, blocked HHV-8 DNA replication at a fourfold-lower concentration than did foscarnet (EC50 of 39 and 177 microM, respectively). The most potent inhibitory effect was obtained with the N-7-substituted nucleoside analog S2242 (EC50, 0.11 microM). The nucleoside analogs acyclovir, penciclovir, H2G ((R)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine), and brivudine had weak to moderate effects (EC50 of > or =75, 43, 42, and 24 microM, respectively, and EC90 of > or =75 microM), whereas ganciclovir elicited pronounced anti-HHV-8 activity (EC50, 8.9 microM).