Inhaled iloprost has proven to be an effective therapy in patients with pulmonary hypertension (PH). However, the acute hemodynamic effect of nebulized iloprost delivered via the I-neb Adaptive Aerosol Delivery (AAD) system remains unclear and needs to be assessed. In this study, 126 patients with PH were classified according to current guidelines (59, 34, 29, and 4 patients in groups 1/1′, 3, 4, and 5, respectively; 20 patients had idiopathic pulmonary arterial hypertension [iPAH]), were randomly assigned to inhale iloprost 2.5 μg (n = 67) or 5.0 μg (n = 59) via the I-neb AAD system, and were assessed by right heart catheterization. In seven patients with iPAH, iloprost plasma levels were measured. The two iloprost doses caused decreases from baseline in pulmonary vascular resistance (PVR; 2.5 μg: −14.7%; 5.0 μg: −15.6%) and mean pulmonary arterial pressure (mPAP; 2.5 μg: −11.0%; 5.0 μg: −10.1%) while cardiac index (CI) increased (2.5 μg: +6.5%; 5.0 μg: +6.4%). The subset with iPAH also showed decreases from baseline in PVR and mPAP and an increase in CI. Peak iloprost plasma levels showed no significant difference after inhalation of 2.5 μg or 5.0 μg iloprost (95.5 pg/mL vs. 73.0 pg/mL; P = 0.06). In summary, nebulized iloprost delivered via the I-neb AAD system reduced mPAP and PVR and increased CI from baseline in a heterogeneous group of patients with PH and in the subset with iPAH. In patients with iPAH, inhalation of 2.5 μg or 5.0 μg iloprost resulted in broadly similar peak iloprost plasma levels.