An impairment in lymphocyte response to mitogen stimulation, a correlate of cell-mediated immunity, has been reported in patients with depressive illness. To investigate whether such impairment in lymphocyte function is related to excessive secretion of cortisol, an immunosuppressive hormone, we compared mitogen-induced lymphocyte proliferation in three groups of subjects: depressed patients with elevated 24-hour urinary free cortisol (UFC) excretion; depressed patients with normal UFC excretion; and normal controls. Depressed patients in both groups showed significant reductions in lymphocyte mitogenic activity, in comparison with the normal controls, but the two depressive groups did not significantly differ from each other in their lymphocytic responses to any of the mitogens used. Furthermore, no significant correlations were found, within depressed patients, between UFC excretion and lymphocyte mitogenic responses. Depression is therefore associated with an impairment in lymphocyte function that cannot be explained solely on the basis of increased cortisol secretion.