Pulmonary arterial infusion of prostaglandin E2 (mean dose, 1 microgram/kg/min) in term neonatal lambs ventilated with room air resulted in a slight fall in pulmonary arterial pressure (P less than 0.05). Infusion during ventilation with low oxygen mixtures resulted in a parallel fall in pulmonary and arterial pressures and resistances. Intrapulmonary infusion of acetylcholine (mean dose, 3.9 microgram/kg/min) in lambs during ventilation with room air caused a slight fall in mean systemic arterial pressure and systemic vascular resistance. When repeated with low oxygen ventilation, infusion of acetylcholine caused a parallel fall in both pulmonary and systemic arterial pressures and resistances. Infusion of tolazoline at a mean dose of 0.21 mg/kg/min did not change pulmonary or systemic arterial pressures or resistances when the lambs were ventilated with room air or with hypoxic gas mixtures although individual animals experienced marked falls in systemic arterial pressure. Pulmonary arterial infusion of each of the three vasodilators during hypoxic ventilation resulted in potentially adverse hemodynamic effects. This occurred despite prior ductal ligation, implying that doses effective for pulmonary vasodilation may exceed doses without systemic effects particularly in the acute hypoxic state.