The immune reactivity of patients with squamous carcinoma of the head and neck region was compared with that of patients with squamous carcinoma of the female pelvic organs and patients with adenocarcinomas, melanomas, and sarcomas. The reactivity of patients with clinically localized tumors was compared with that of cured patients and a large normal population. Patients with squamous carcinomas of the head and neck region and female pelvic organs displayed higher incidences of impaired cellular immune competence than patients with malignancies of other histologic types. Among cured patients, those previously treated for squamous carcinoma were unique in that they displayed cellular immune defects and serum suppressants of in vitro immune reactivity similar to tumor-bearing patients. Antibodies to herpes simplex virus nonvirion antigen was found in high incidence only among patients with squamous carcinomas, and the incidences in tumor-bearing and cured patients were similar. The persisting immune defects in cured squamous carcinoma patients give importance to the determination of the role of genetic and environmental factors in the induction of these tumors. The associations made between herpes virus and squamous carcinoma offer an explanation for the defects and also an approach for the definition of the factors involved in squamous carcinogenesis. The findings are clinically relevant to the isolation of population groups at high risk for the development of squamous carcinoma, as a rational basis for the development of prophylactic measures, and as a basis for more effective therapeutic regimens.