The relation between herpes simplex virus (HSV) and head and neck cancer was examined. A total of ninety patients were analyzed for IgG antibodies against HSV. Antibody titers were established with an enzyme-linked immunosorbent assay and antibodies against specific HSV-antigens were analyzed by Western blot. These patients' seroreactivity was compared to that of an age-matched control group of patients with arteriosclerotic disease in their lower limbs, a disease also closely related to heavy tobacco consumption. Prevalence of antibodies against HSV was around 90% and did not differ significantly between cancer patients and controls, but antibody titers against HSV were significantly higher in the cancer patients. The cancer patients also reacted more constantly (80%) in Western blot analysis against the early immediate protein, ICP-4, than controls (50%). This suggests a different course of an earlier herpetic infection in these patients with a prolonged exposure to early immediate HSV-proteins which may be related to an increased risk of developing head and neck cancer. We propose that heavy smoking may contribute to this phenomenon.