The inhibitory effects of interferon (IF) on the replication of varicella-zoster (VZ) virus in human foreskin fibroblast (HFF) cultures inoculated with infected cells or with cell-free virus were assayed by measuring (1) yields of infected cells, (2) plaques, (3) microfoci and (4) cytopathic effects. More IF was needed to reduce yields of infected cells at high input multiplicities of challenge than at low input multiplicites, and still more IF was needed to prevent cytopathology due to VZ virus. A cell-free virus inoculum was more sensitive to the inhibitory effects of IF than an inoculum of infected cells. With the latter, but not with cell-free virus, the continuous presence of IF in the medium was necessary for it to express its maximum antiviral activity. To explain these results, it is suggested that some herpesviruses may establish "reservoirs' of infectivity and thus provide a prolonged challenge to IF-treated cells which are not uniformly resistant to infection.