Varicella-zoster virus (VZV) directs the synthesis of a nonglycosylated polypeptide complex with two prominent species with relative molecular masses of 32,000 and 36,000; the p32/p36 complex is present in both the viral nucleocapsid and the nuclear matrix of the infected cell. We have now further characterized the humoral immune response of VZV-infected humans to this complex and established that it is a major viral antigen. Antibodies to VZV p32/p36 were detected in sera from patients with both primary VZV infection (chickenpox) and VZV reactivation (zoster); the response after zoster was more pronounced. When the IgM and IgG components of the immune response were distinguished, IgM to the viral nucleoproteins was observed following chickenpox and zoster and, to a lesser extent, in recipients of VZV vaccine. An IgM response to VZV p32 also was detected during intrauterine VZV infection and subclinical VZV infection.