The effect of prostaglandin E2 (PGE2) on the fetal circulation was measured in chronically catheterized ewes using radioactive microspheres. The injection of 10 mug/kg PGE2 into six fetuses resulted in a biphasic pressor response with a hypotensive period followed by a prolonged period of hypertension. The fetal arterial pressure rose from 45 to 63 mmHg (P less than 0.002). The placental membrane flow changed from 36 to 16 ml/min (P less than 0.004), the fetal renal blood flow changed from 8.6 to 7.1 ml/min per kg of fetus (P less than 0.001). It was postulated that the hypotensive response was due to a direct effect of PGE2 on the heart and the hypertensive response was due to PGE2 releasing a vasoconstricting agent into the fetal circulation. In nine experiments the PGE2 was administered to the maternal lcirculation. This caused a fetal hypertension and a vasoconstriction of the fetal renal, placental membrane, and umbilical circulations. These changes were similar in time course and magnitude to those described above. It is postulated that PGE2 crosses the placenta and that the fetal responses seen in this series are similar to those seen when PGE2 is administered to the fetal circulation.