To investigate the impact that physiological variation in serum cortisol has on IgE-mediated events, 10 atopic subjects underwent cutaneous antigen challenge with measurement of the early phase wheal (EPW) at 20 min and the late phase reaction (LPR) at 6 h. All subjects were challenged during control conditions between 8:00 and 9:00 a.m. Repeat challenges were performed in five subjects at 6:00 p.m. and in eight subjects after ingestion of metyrapone, a specific inhibitor of cortisol synthesis. Compared with control values, mean serum cortisol was suppressed in the evening and after metyrapone (P less than 0.05 all time points). No effect was seen on the EPW, but mean LPR diameters at three antigen dilutions were significantly increased by cortisol suppression (P less than 0.05). Replacement doses of hydrocortisone given in the evening and with metyrapone abrogated these increases. Blinded analysis of LPR biopsies from cortisol-suppressed subjects revealed increases in leukocytoclasis (P less than or equal to 0.0001), interstitial leukocytes (P less than or equal to 0.01), and eosinophils (P less than or equal to 0.04). These results indicate that physiological levels of serum cortisol can regulate IgE-dependent cutaneous inflammation by affecting the expression of cellular events at late phase sites.