We are interested in understanding the pathogenesis of the cutaneous IgE-mediated late phase reaction. A double-blind, placebo-controlled, randomized cross-over study with 10 subjects of the effect of the non-sedating antihistamine, terfenadine (Selddane), on the cutaneous reaction to antigen (ragweed or mixed grass) administered intradermally and over denuded blister bases was performed. The activity of terfenadine on anti-IgE-induced mediator release from the skin mast cell, lung mast cell and basophil was also examined in vitro. Terfenadine significantly inhibited the size of the cutaneous reaction at every hour between hours 1 and 9 (hr 9, control 2250 ± 500 mm2vs drug 1250 ± 250 mm2, P < 0.01, n=10) and showed some inhibitory effect at hours 10–12. While terfenadine blocks histamine release after nasal antigen challenge the release of mediators at skin blister sites was unaffected. The infiltration of leucocytes into the blister supernatant was unaffected by terfenadine although previous studies have shown significant inhibition with another antihistamine, cetirizine. In vitro, terfenadine. like other antihistamines, was found to have inhibitory activity on anti-IgE-induced mediator release at concentrations of 10−4-10−5 M in lung and skin mast cells and basophils. We conclude that the effects of the newer antihistamines on cellular movement into the skin may be diverse, that terfenadine may show organ specificity in vivo and that terfenadine significantly decreases both the early and late gross inflammatory response of the skin to antigen. We cannot, as yet. explain the mechanism(s) by which this occurs.