Thirty depressed psychiatric inpatients, including 18 with a diagnosis of major depression, and 25 hospital staff controls were compared with respect to cellular immune function--that is, mitogen responsiveness to concanavalin A (con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM); natural killer cell (NK) activity; and T cell subsets, including helper/inducer T cells (CD4) and suppressor/cytotoxic cells (CD8). Only physically healthy subjects, who had not used psychoactive medications (except for low dose benzodiazepines) or other medications known to affect the immune system for at least 14 days, were included. Paired comparisons of the immune measures of patients with a DSM-III diagnosis of major depression (n = 18) with their controls demonstrated a statistically significant reduction of the patients' con A response. In addition, the patients with major depression had significantly lower con A and PHA responses than the combined patients with other forms of depression (atypical, dysthymic, or atypical bipolar). There was no indication that severity of depression, dexamethasone suppression test status, benzodiazepine use, or age accounted for the differences in immune function. A possibly important, unexpected finding was that antihistamine use was associated with lower immune function.