We investigated the effect of misoprostol on allergen-induced cutaneous immediate- and late-phase allergic reactions in a double-blind placebo-controlled randomized study. Sixteen dust-mite-allergic patients received misoprostol (200 &mgr;g) or placebo and then had skin testing on two different days. The immediate- and late-phase skin response was monitored for 6 h. Skin biopsy was obtained from five selected donors at 5 h. In vitro studies included the effect of misoprostol on eosinophil chemotaxis, eosinophil survival, basophil histamine release, and cytokine production by lymphocytes. All subjects developed an immediate wheal reaction and a late-phase induration in response to dust-mite allergens after taking placebo. Misoprosol selectively inhibited the late-phase but not the immediate-phase response (p < 0.05). Histologic studies revealed a trend toward a reduced number of inflammatory cells in the skin dermis after misoprostol treatment. We also investigated the mechanism of action of misoprostol in vitro. Misoprostol significantly (p < 0.05) inhibited eosinophil chemotaxis and the production of granulocyte/macrophage colony-stimulating factor by lymphocytes at concentrations greater-than-or-equal10(minus sign8) M. However, at significantly lower concentrations (greater-than-or-equal10(minus sign12)M), misoprostol blocked cytokine-stimulated eosinophil survival. Thus, misoprostol has potent antiallergic effects and blocks the cutaneous late-phase allergic inflammation.