Antibody responses to early antigens of varicella-zoster virus (VZV), simian varicella virus, and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) were studied in primary, secondary, and latent infections. IgG antibody responses to the early antigens occurred in primary and secondary VZV and HSV infections, and antibodies to early antigens were also demonstrable in healthy individuals with latent VZV and HSV infections, indicating that the presence of antibodies to early antigens cannot be taken as evidence of active infection with the viruses. Patients with current VZV or HSV infections showed heterotypic IgG antibody responses to early antigens of VZV and HSV to the same extent as to late antigens. In all groups of patients, IgG antibody titers to early antigens were similar to those against the corresponding late antigens, and no difference was seen in the reactivity of early antigens produced with four different blocking agents (cytosine arabinoside, bromodeoxyuridine, trisodium phosphonoformate, and cycloheximide). Antibodies of the IgM and IgA classes reacted with both early and late antigens of HSV, but only with late antigens of VZV and simian varicella virus, suggesting that these antibodies may be directed against late proteins that are expressed to a greater extent in HSV-infected cells treated with blocking agents than they are expressed in treated VZV-infected cells. Homologous IgM antibody responses occurred in both primary and secondary VZV infections, but only in primary HSV infections. Heterotypic IgM responses to HSV-2 antigen were noted in a few VZV patients who did not have demonstrable IgG antibody to HSV, suggesting that even in patients without prior experience with HSV, a VZV infection may stimulate the production of IgM antibodies that react with antigens that are shared by VZV and HSV-2. IgA antibodies to late antigens of VZV and HSV were demonstrable in latent, as well as active, infections with these viruses.