Major depression and dysthymia have been associated with increased perception of day-to-day stressors, greater reliance on emotion-focused coping efforts, and reduced perception of uplifting events. Moreover, it has been observed that levels of circulating natural killer (NK) cells were elevated in depressed patients. Given that mild stressors may increase circulating NK cells, it is conceivable that the elevated NK cells in depression may be secondary to the increased stress perception associated with the illness. In the present investigation a laboratory stressor, comprising a mathematical challenge, increased circulating NK cells; however, the extent of the increase was comparable in depressive, dysthymic and control subjects. Moreover, the increased NK cells induced by the stressor procedure appeared to be independent of variations of plasma cortisol, ACTH or norepinephrine. Interestingly, although the NK changes were not differentially influenced by stressors in the subject populations, in the major depressive patients correspondence existed between NK cell levels and emotion-focused coping styles. Likewise, the response to a laboratory stressor was directly related to the severity of depression and to the use of coping styles involving cognitive restructuring or problem solving.