In this double-blind study we have investigated the vascular effects of prostaglandin, (PG) D2, in normal skin and compared these effects with histamine and the initial PGD2 metabolite 9α, 11β-PGF2. In eight healthy subjects the vascular response to intradermal injections of histamine, PGD2, a combination of histamine and PGD2, and 9α, 11β-PGF2, was assessed by measurement of the weal and flare area. Histamine caused dose-related increases in weal area (P<0.01). The weal response due to PGD2 was greater than saline control only at a dose of 71.0 and 710 nmol (P<0.05). Because of the small size of the weal produced by PGD2 when compared with histamine, it was not possible to determine their relative potencies. Histamine and PGD2 caused dose-related increases in flare area (P<0.05), and when compared at a response level of 10 cm2 and 15 cm2, histamine was 45 and 251 (P<0.01) times more potent than PGD2 in molar terms. Weal and flare responses due to 9α, 11β-PGF2 were similar to those observed with the equimolar concentration of PGD2. The weal and flare responses when PGD2 and histamine when combined were not significantly different from that predicted by a purely additive effect. We conclude that histamine is likely to be an important mediator contributing towards increased vascular permeability and vasodilatation following immunological activation of skin mast cells in vivo, while PGD2 and its metabolite 9α, 11β-PGF2 play only a minor role.