Immunological responses of patients with recurrent herpes genitalis (RHG) were assayed in comparison to those of patients affected by recurrent herpes labialis (RHL) and to those of normal seropositive and seronegative controls. Total T cells were normal while a significant (p less than 0.001) reduction of cells with helper phenotype was found only in people with RHG, who were also lacking specific cell-mediated immunity (CMI) to herpes simplex virus (HSV) antigen. HSV-type 2 was demonstrated in their active lesions. Number of human NK-1 positive (HNK-1 +) cells was increased in RHG showing an inverse correlation with depressed natural killer (NK) activity. These abnormalities were found irrespective or not if tests were carried out during the active phase of the disease or during quiescence and were confirmed during the 2-year follow-up period to which patients were submitted. Similar abnormalities were found in RHL only during the active phase and reversed to normal during quiescence. Our data indicate the presence of specific cellular and NK unresponsiveness in subjects with severe and long-lasting herpes genitalis.