The effect of in vivo hydrocortisone (OHC) on natural killer (NK) activity was studied using the K562 cell line as target in a 3-h 51Cr-release assay. Peripheral blood lymphocytes obtained from five normal volunteers at 0, 4, 24 and 48 h after intravenous administration of 300 mg of OHC showed significantly increased NK activity at 4 h, decreased activity at 24 h, with a return toward normal at 48 h. Parallel variations were found in the fraction of lymphocytes bearing receptors for the Fc part of IgG. However, neither the number of these cells nor the NK activity was influenced by the medication when the results were given per millilitre blood. In vitro preincubation of the effectors with OHC for 24 h had no effect on viability, expression of surface markers, or NK activity. It is concluded that under the present conditions NK activity is OHC-resistant. The variations observed after in vivo administration seem to be due to a reversible redistribution mainly affecting cells other than the NK effectors.