By indirect immunofluorescence, enzyme-linked immunosorbent assay, and in vitro lymphocyte proliferation, we studied the antibody and cell-mediated immune response to varicella zoster virus (VZV) in serum, peripheral blood lymphocytes, and tonsillar lymphocytes in 49 children before and after tonsillectomy and adenoidectomy. Among the naturally infected patients seropositive for VZV antibody, most demonstrated VZV-specific proliferation in the peripheral blood and tonsillar lymphocytes, with activity consistently higher in the tonsillar lymphocytes. Several patients seronegative for VZV antibody and without a prior history of clinical chickenpox also manifested VZV-specific proliferation in the tonsillar lymphocytes, and less frequently in peripheral blood lymphocytes. Of these, six children with high levels of activity in tonsillar lymphocytes, with or without high levels in the peripheral blood lymphocytes, failed to develop disease after intimate exposure to VZV in family settings. On the other hand, three other subjects with little or no VZV-specific proliferative activity in the tonsillar lymphocytes developed disease after similar exposure to VZV. These observations suggest the development of VZV-specific mucosal cellular immunity after overt or inapparent exposure to VZV. The appearance of such immunity appears to have a protective role against reinfection even in the absence of detectable serum antibody.