Eighteen normal male subjects were recruited for a double-blind, placebo-controlled, randomized, two-period crossover study to determine the effects of a new, potent, highly selective, oral peptide leukotriene antagonist (ICI 204,219) on cutaneous vasculature. Skin testing for leukotriene D4 (LTD4) and histamine was performed at three different time intervals after receiving ICI 204,219 or placebo. The LTD4 threshold dose responses were recorded in duplicate to verify reproducibility. These data confirm known remarkable dose-response variation of cutaneous vascular reactions to LTD4 since some subjects reacted to a dose as low as 0.001 fmol. Twelve subjects (67%) demonstrated a more than one-half log increase in their threshold response after receiving ICI 204,219. Five of these 12 subjects (28%) had greater than 1 log-dose response after ICI 204,219. Two of these subjects (11.1%) had a 5 or 10 log increase in their threshold response after receiving ICI 204,219. Given the role of leukotrienes as potentially important mediators in immediate-type reactions, our results raise the possibility for additional investigation of the antagonistic effect of ICI 204,219 in nonallergic and allergic cutaneous diseases.