Abstract Background Ischemia-reperfusion injury accounts for one-third of early deaths after lung transplantation. To expand the limited donor pool, lung retrieval from non-heart-beating donors (NHBD) has been introduced recently. However, because of potentially deleterious effects of warm ischemia on microvascular integrity, use of NHBD lungs is limited by short tolerable time periods before preservation. After intravenous prostanoids are routinely used to ameliorate reperfusion injury, the latest evidence suggests similar efficacy of inhaled prostacyclin. Therefore, the impact of donor pretreatment with the prostacyclin analogue iloprost on postischemic NHBD lung function and preservation quality was evaluated. Methods Asystolic pigs (5 per group) were ventilated for 180 minutes of warm ischemia (Group 2). In Group 3, 100 μg iloprost was aerosolized during the final 30 minutes of ventilation with a novel mobile ultrasonic nebulizer. Lungs were then retrogradely preserved with Perfadex and stored for 3 hours. After left lung transplantation and contralateral lung exclusion, hemodynamics, rO 2/F iO 2, and dynamic compliance were monitored for 6 hours and compared with sham-operated controls (Group 1). Pulmonary edema was determined both stereologically and by wet-to-dry weight ratio (W/D). Statistics comprised analysis of variance with repeated measures and Mann-Whitney test. Results Flush preservation pressures, dynamic compliance, inspiratory pressures, and W/D were significantly superior in iloprost-treated lungs, and oxygenation and pulmonary hemodynamics were comparable between groups. Stereology revealed a trend toward lower intraalveolar edema formation in iloprost-treated lungs compared with untreated grafts. Conclusions Alveolar deposition of Iloprost in NHBD lungs before preservation ameliorates postischemic edema and significantly improves lung compliance. This easily applicable innovative approach, which uses a mobile ultrasonic nebulizer, offers an important strategy for improvement of pulmonary preservation quality and might expand the pool of donor lungs.