15-Hydroxyeicosatetraenoic acid (15-HETE), a 15-lipoxygenase product of arachidonic acid, inhibits leukotriene B4 (LTB4)-induced chemotaxis of polymorphonuclear leukocytes (PMNs) in vitro. In this study the effects of intradermal injections of LTB4 were determined in the absence or presence of 15-HETE. For comparison intradermal injections of purified human complement split product C5a were performed in the absence or presence of 15-HETE. The skin response was evaluated by measuring the diameter of the wheal, the area of the flare and by intensity of the erythema (erythema index). LTB4 and C5a were injected at the concentration of 200 ng/ml. At this concentration the maximal skin response of LTB4 and C5a were equivalent. In contrast to C5a reaction, which resolved within 1 h, LTB4-induced skin response lasted up to 18 h. In all subjects the skin response was significantly decreased when LTB4 was injected together with 300 ng of 15-HETE. The decrease of wheal, flare, and erythema index averaged 81.9%, 56.6%, 53.6%, respectively, when all parameters were obtained at the maximal skin response. In contrast, the C5a-induced skin response was not affected by addition of 15-HETE, even when the final dose of 15-HETE was increased 10 times to 3 micrograms. The LTB4-induced reaction could last up to 18 h after injection. After the addition of 300 ng of 15-HETE the skin response resolved after 1 h. The present results demonstrate that 15-HETE is a specific inhibitor of the LTB4-induced skin response and brings additional evidence in support of the ability of 15-HETE to regulate the proinflammatory effects of LTB4 in vivo.