We recently showed that patients with active ileocecal Crohn's disease (CD) have a temporarily suppressed peripheral blood natural killer (NK) cell activity during treatment with oral budesonide or prednisolone. This suppression was caused by a decrease in the number of CD16+ NK cells in the circulation. In the present study we evaluated the contribution of cortisol in plasma to this suppressed NK cell activity. The CD patients took part in a controlled study where they received either oral budesonide or prednisolone for 10 weeks. Before treatment, and at 4 and 10 weeks of treatment, peripheral blood NK cell activity, numbers of circulating CD16+ NK cells, and plasma cortisol levels were analysed. These parameters were determined both before and 30 min after administration of adrenocorticotropic hormone (ACTH). The ACTH-induced plasma cortisol increase was accompanied by a stimulated NK cell activity, when both are suppressed by corticosteroid treatment, without changing the number of CD16+ NK cells. Therefore, a low plasma cortisol level contributes to the corticosteroid mediated NK cell suppression in active ileocecal CD.