Neutralizing antibody to Herpes simplex virus type 1 (HSV-1), type 2, and measles virus was measured in the serum of patients with oral cancer, patients with oral leukoplakia, and in control subjects who were smokers and nonsmokers. Significantly higher titers to HSV-1 were found in controls who smoked than in controls who did not smoke. Patients with untreated oral cancer had HSV-1 neutralizing titers similar to those of the controls who smoked, but those with later stage tumors had higher titers than those with earlier stage tumors. In patients who were tumor free after treatment for oral cancer, higher antibody titers to HSV-1 were associated with longer survival times. No association was found between clinical status and antibody to measles virus. The data are consistent with a role for both HSV-1 and smoking in the pathogenesis of oral cancer.