To test the hypothesis that prostaglandin (PG) E2 is a respiratory depressant in the newborn lamb, 12 chronically catheterized, unanesthetized lambs (age 2 to 6 days) were infused with progressively increasing doses of PGE2 (0.1, 0.5, 1.0 and 5.0 ug/kg/min: 30 min for each dose) into the ascending aorta. PGE2 caused significant, progressive decrease in ventilation (due to decreased tidal volume and breathing rate) heart rate, blood pressure and percent of the time spent in low voltage electrocortical activity (LVA). PGE2 also caused respiratory acidosis, hypoxemia and increased frequency and duration of apneic events (greater than 3 sec). During the infusion, there was a dose related increase in plasma concentration of PGE2. At 30 min post-infusion, all measured variables showed recovery, although arterial pH carbon dioxide tension and plasma PGE2 remained significantly different from control values and the percent time in LVA was even higher than during control. Infusion of the vehicle alone (n = 5) caused no significant changes in any of the measured variables. The results, taken in combination with previous fetal studies, indicate that PGE2 has marked inhibitory effects on breathing movements both before and after birth.