Inhalation of aerosolized iloprost, a stable prostacyclin analog, has been suggested for treatment of primary and secondary pulmonary hypertension, but demands multiple daily inhalation maneuvers because of the short-term effect of this approach. In intact rabbits, pulmonary hypertension was induced by continuous infusion of the stable thromboxane mimetic U46619. Thereafter, the influence of aerosolized iloprost on pulmonary and systemic hemodynamics and gas exchange was investigated in the presence and absence of phosphodiesterase (PDE) inhibitors for stabilization of the second-messenger cAMP. First, dose-effect curves for pulmonary artery pressure (Ppa) decline were established for the nonspecific PDE inhibitors pentoxifylline and dipyridamole and for the dual-selective PDE3/4 inhibitor tolafentrine when being applied as sole agent, either via the intravenous or the inhalative route. Subthreshold doses for each agent and each route of administration were then combined with a standardized iloprost aerosolization maneuver, which resulted in a substantial prolongation, but not augmentation, of the lung vasodilatory response for the prostanoid. Next, higher doses of each PDE inhibitor were employed for nebulization, causing per se some pulmonary vasodilative effect, in the absence of arterial pressure decrease or impairment of gas exchange. Coaerosolization of these PDE inhibitor doses with standardized iloprost caused approximate doubling of the immediate pulmonary vasodilator response, marked prolongation of the pressure relief overtime, and a 2- to 4-fold increase in the area under the curve of pulmonary vasodilation (efficacy tolafentrine > dipyridamole > pentoxifylline). Still, systemic arterial pressure was not suppressed and gas exchange was fully maintained. We conclude that coadministration of PDE inhibitors with inhaled iloprost markedly enhances the prostanoid-induced pulmonary artery pressure decrease while maintaining the lung selectivity of the vasodilatory response, and that coaerosolization is a particularly suitable route of administration. Even nonselective clinically approved PDE inhibitors may be employed for this purpose.