The inhibitory effects of topical glucocorticosteroid treatment on the immediate dermal allergic reaction were studied in 10 patients in a double, randomized, placebo-controlled fashion. The aim was to study whether a prolongation of the treatment time would enhance the inhibitory effect beyond the 30–40% reduction previously reported after I week of treatment, and whether any changes in skin reactivity were accompanied by changes in the level of mast cells or histamine at the challenge site. Allergen and histamine skin-prick tests were performed on both forearms before the start of the study and after 2 and 4 weeks of treatment with placebo cream on one forearm and with 0.05% clobetasot-17-propionate cream on the other. Punch biopsies from the skin treated actively and with placebo were taken after 4 weeks in eight of the patients. The specimens were used for the light-microscopic evaluation of mast cell density and for the measurement of histamine and protein content. After 4 weeks of treatment we found a reduction in the allergen-induced weal (72%; P<0.001) and flare (62%; P<0.05) response. There was also a minor reduction in the histamine-induced weal (38%; P<0.05) but not the flare response, suggesting that the glucocorticoid treatment induced a reduced mediator release at allergen challenge. This could be partially explained by the finding of a reduction in the number of detectable skin mast cells (85%; from 0.78 to 0.11 mast cells per unit area) and in the histamine content of the skin as related to the tissue wet weight (36%; P<0.05). There was also an increase in the protein content of the skin in relation to tissue weight (37%; P<0.05), which was presumably partly caused by a reduction in the water content of the skin, further enhancing the reduction of histamine when related to tissue protein content to 56% (P<0.01). These findings of a glucocorticosteroid induced reduction in the mast cell density of the skin differ from the results of our previous study of airway mucosa, where the mast cell density was not reduced by topical glucocorticoid treatment in a dosage which effectively inhibits the immediate allergic response after allergen challenge. These differences can be interpreted as being due to differences in the steroid responsiveness of different mast cell populations, but may also depend on differences in the pharmacokinetics of the glucocorticosteroids when applied locally to the skin as opposed to the airway mucosa. The present results emphasize the role of the mast cell and histamine in the pathogenesis of the immediate dermal allergic reaction, but also stress that the effects of glucocorticosteroids are largely dependent not only on dosage but also on treatment times. Results from in-vitro and other studies involving short-term treatment with glucocorticosteroids should therefore be interpreted with caution.