Trypsin-induced DNA release from phytohemagglutinin (PHA)-stimulated human lymphocytes is inhibited by different glucocorticosteroid compounds at low pharmacologic concentrations, in a dose-dependent manner, and in order of the known anti-inflammatory potency of the different preparations. In contrast, PHA-stimulated cell growth is 100- to 1000-fold less sensitive to inhibition by the same glucocorticoids. Nonglucocorticoid steroids have little effect on either DNA release or cell growth except at high concentrations. Inhibition of DNA release appears to be mediated through glucocorticoid receptors since progesterone, which is ineffective alone, competitively inhibits the effect of dexamethasone. The glucocorticoid effect on DNA release is tightly coupled to the initial, PHA-induced stimulus. Glucocorticoids are maximally effective when added to cultures 1 hr before PHA. When added 6 hr after PHA, their effect is minimal or absent, even though they are then continuously present until DNA release is measured 5 days later. Lymphocytes from certain donors in these studies were resistant to glucocorticoids; these individuals all had allergies, including asthma, allergic rhinitis, and bee sting hypersensitivity.