Leukotriene B4 (LTB4) is a potent proinflammatory arachidonic acid metabolite whose actions are mediated by specific receptors. Recent characterization of a high-affinity LTB4 receptor on the surface of guinea pig CD4+ T lymphocytes prompted examination of a possible role of LTB4 in modulating in vivo expression of delayed-type hypersensitivity (DTH) to tuberculin (PPD). In the absence of PPD, intradermal injections of LTB4 or LTB4/LTD4 receptor antagonists did not elicit delayed-onset erythema at 24 h. When injected together with PPD, LTB4 (1 fmol to 1 pmol) caused a significant 25 to 30% decrease in DTH expression, whereas LTB4 receptor antagonists SC-41930, LY-223982, ONO-4057 (0.1-10 nmol), caused a highly significant (P < .01) 25 to 50% increase. The effect of SC-41930 on DTH expression was inhibited by a 10-fmol dose of LTB4. LTD4 receptor antagonist LY-171883 had no effect on DTH expression. Lipoxin A4 (LXA4) interferes with binding of LTB4 to T lymphocytes or neutrophils by reducing LTB4 receptor density. It caused a small but significant enhancement of DTH expression at 1-nmol doses when injected with PPD. Lipoxin B4 had no effect. Enhancement or inhibition of grossly visible delayed skin responses to PPD by LTB4. LTB4 receptor antagonists or LXA4 was not associated with qualitative or quantitative changes in superficial or deep dermal mononuclear cell infiltrates at the reaction site. We conclude that LTB4 modulates visible expression of DTH in vivo by a receptor-mediated mechanism.