Replication of varicella-zoster virus (VZV) and expression of VZV nuclear antigen are inhibited in human embryonic lung fibroblast (HEL) cells pretreated with recombinant tumor necrosis factor (TNF) alpha for 24 h. This antiviral activity is completely blocked by the addition of monoclonal antibodies against TNF. TNF acts synergistically with interferons alpha and gamma. When TNF is added to HEL cells after VZV adsorption, virus replication is still inhibited. When VZV-infected HEL cells are co-cultured with HEL cells which have been pretreated with TNF or grown in the presence of TNF, spread of VZV from VZV-infected HEL cells to uninfected cells is unaffected. No interferon is detected in the supernatants or cell lysates of HEL cells cultured with TNF and antibodies to alpha-, beta- and gamma-interferon have no effect on the antiviral action of TNF.