In a prospective study of squamous head and neck cancer, the pretreatment peripheral blood of 125 patients was examined for lymphocyte subclass and in vitro immunologic function. After 4 years of follow-up, 49 recurrences of disease were observed. Lymphocytes from patients with recurrent disease showed elevated interleukin-2 (IL-2) production and a tendency towards increased response to mitogens in comparison to those without recurrence. When disease-free survival is analyzed on the basis of IL-2 levels, patients with high relative IL-2 synthesis (greater than or equal to 1) had a 40% poorer prognosis than patients with low relative IL-2 levels (less than 1). The difference is significant at a P value of 0.02. Since IL-2 synthesis occurs with antigenic stimulation, it is postulated that patients who have a high IL-2 synthesis in their pretreatment lymphocytes may have had prior stimulation by circulating tumor antigen. Such immune response by the host may be successful in destroying the antigenic tumor cells but may leave the undifferentiated, less antigenic tumor cells to grow and metastasize. Thus, elevated IL-2 synthesis in pretreatment lymphocytes predicts a poorer prognosis.