An association between depression and altered immunity has been suggested but has not been consistently demonstrated. We have studied 91 patients with unipolar major depressive disorder, and no mean differences were found between the patients and concurrently studied matched controls in mitogen-induced lymphocyte proliferation, lymphocyte subsets, and natural killer cell activity. There were, however, significant age-related differences between the depressed patients and controls in mitogen responses and in the number of T4 lymphocytes. In contrast to age-related increases in mitogen response and in T4 cells in controls, depressed patients did not show increased lymphocyte responses or numbers of T4 lymphocytes with advancing age. Severity of depression and hospitalization status were also associated with immune system changes. Altered immunity does not appear to be a specific biologic correlate of major depressive disorder but may occur in subgroups of depressed patients.