Little is known about the possible role of leukocytes in the pathogenesis of vasospasm. We hypothesized that vasoactive products released by leukocytes might produce constriction of atherosclerotic arteries. To test this hypothesis, we infused fmet-leu-phe (fMLP), a peptide that activates leukocytes to release their vasoactive products, into the perfused hind limb of normal and atherosclerotic cynomolgus monkeys. Infusion of fMLP did not change resistance of large arteries in normal monkeys. In contrast, fMLP produced pronounced constriction of large arteries in atherosclerotic monkeys. To determine whether leukotrienes, platelet-activating factor, or prostaglandin E2 (PGE2), which are released by leukocytes, may contribute to leukocyte-induced vasoconstriction in atherosclerotic monkeys, we injected leukotriene D4, platelet-activating factor, and PGE2 intra-arterially into the perfused hind limb. Leukotriene D4 and platelet-activating factor had minimal effects on large arteries in both normal and atherosclerotic monkeys. PGE2 produced marked constriction of large arteries in atherosclerotic, but not normal, monkeys. Thus, pronounced constriction in atherosclerotic, but not normal, arteries during infusion of fMLP suggests that products released by leukocytes may mediate vasoconstriction in atherosclerotic vessels. Vasoconstrictor responses to PGE2 are profoundly potentiated by atherosclerosis, which suggests that PGE2 may contribute to leukocyte-induced vasoconstriction.