OBJECTIVE: We tested the hypothesis that trophoblast produces 15- hyroxyelcosatetraenoic acid, and its level is elevated in trophoblast from preeclamptic women compared with normal. We also used selective enzymatic inhibitors to determine the relative contributions of 15-lipoxygenase and the two isozymes of prostaglandin H synthase to 15-hydroxyeicosatetraenoic acid levels. STUDY DESIGN: Cytotrophoblasts isolated from placentas of normal or preeclamptic women were cultured in the presence or absence of enzyme inhibitors. Media levels of 15-hydroxyeicosatetraenoic acid were measured by radioimmunoassay. RESULTS: When compared with normal pregnancies, cytotrophoblasts from preeclamptic pregnancies released up to fivefold higher levels of 15-hydroxyeicosatetraenoic acid. Aspirin, an inhibitor of both the prostaglandin H synthase-1 and prostaglandin H synthase-2 isozymes, and nordihydroguaiaretic acid, a selective inhibitor of lipoxygenases, both significantly inhibited 15-hydroxyeicosatetraenoic acid production. In contrast, the selective prostaglandin H synthase-2 inhibitor NS-398 had no effect on 15-hydroxyeicosatetraenoic acid release in the absence of aspirin, but NS-398 reduced 15-hydroxyeicosatetraenoic acid levels in normal trophoblast pretreated with aspirin. CONCLUSION: The data indicate that 15- hydroxyeicosatetreanoic acid is produced in trophoblasts and its release by cytotrophoblasts is higher in preeclamptic pregnancies compared with normal controls. Both lipoxygenase and prostaglandin H synthase contribute to 15- hydroxyeicosatraenoic acid production, and aspirin reduces 15- hydroxyeicosatetraenoic acid secretion. We suggest 15- hydroxyeicosatetraenoic acid plays a role in the oxidation of lipoproteins and the endothelial damage characteristic of preeclampsia.