The vasodilatory response to arachidonic acid by the fetal vessels of human perfused placental lobules, in which tone had been increased by infusion of the thromboxane A2 mimetic U46619, was significantly reduced in the presence of the prostacyclin (PGI2) synthetase inhibitor tranylcypromine compared with saline infusion controls. HPLC analysis of the fetal effluent from human perfused placental lobules, in which radiolabelled arachidonic acid had been infused, identified two peaks of activity. The first peak displayed an elution profile similar to that of a 6-keto-PGF1 alpha standard; the presence of 6-keto-PGF1 alpha in this peak was confirmed by RIA. The second peak had an elution profile similar to that of an arachidonic acid standard. These results suggest that the vasodilatory response to the fetal vessels of human perfused placental lobules to acute infusions of arachidonic acid is mediated, at least in part, by the synthesis of PGI2. These data are consistent with the hypothesis that PGI2 may be involved in the maintenance of low vascular resistance of the fetal placenta in utero.