Penciclovir (PCV) and acyclovir are acyclic guanine analogs which inhibit herpes simplex virus (HSV) DNA polymerase. Their 50% infective doses were 0.5 to 0.8 microgram/ml for clinical isolates of HSV-1 and 1.3 to 2.2 micrograms/ml for HSV-2. Furthermore, HSV-infected cultures receiving 2-h pulses of PCV had 2- to 50-fold less HSV than acyclovir-treated cultures, consistent with the prolonged intracellular half-life of PCV triphosphate.