Nitric oxide (NO) relaxes vascular smooth muscle by increasing the intracellular concentration of cGMP. In the pulmonary circulation, cGMP is inactivated by specific phosphodiesterases (PDE5). Dipyridamole, a clinically approved drug, has inhibitory activity against PDE5 and has been reported to augment the response to inhaled NO in persistent pulmonary hypertension of the newborn (PPHN). We wished to determine whether dipyridamole alone, or in combination with NO, can be used to treat a newborn lamb model of PPHN. In newborn lambs with PPHN, dipyridamole infused at 0.02 mg/kg/min for 45 min alone, or in combination with 5 ppm of inhaled NO for the final 15 min, significantly decreased pulmonary and systemic blood pressure, decreased pulmonary vascular resistance, and increased pulmonary blood flow. There was no significant difference between the pulmonary vascular effects of 5 ppm NO alone compared with the effects of NO combined with dipyridamole. In control lambs, the 45-min infusion of dipyridamole did not change pulmonary pressure whereas systemic pressure decreased by 28 ± 3%. These systemic effects in control lambs persisted 90 min after discontinuing the dipyridamole infusion. Systemic arteries isolated from both control and PPHN lambs were significantly more sensitive to dipyridamole than pulmonary arteries. We conclude that dipyridamole has significant hemodynamic effects in both the pulmonary and systemic circulations of newborn lambs with pulmonary hypertension as well as in the systemic circulation of newborn control lambs. The pronounced effects of dipyridamole on the systemic circulation limits its utility as an adjunct to inhaled NO in the treatment of PPHN.