Rationale The mortality in SARS-CoV-2 infected patients requiring mechanical ventilation remains high and endotheliopathy has been implicated. Objective To determine the effect of prostacyclin infusion in mechanically ventilated SARS-CoV-2 infected patients with severe endotheliopathy. Methods We conducted a multicenter, randomized, clinical trial in COVID-19 infected adults requiring mechanical ventilation having a plasma level of thrombomodulin >4ng/ml who were randomized to 72-hours infusion of prostacyclin 1 ng/kg/min or placebo. Measurements The main outcome was the number of days alive and without mechanical ventilation within 28-days. Key secondary outcomes were 28-day mortality and serious adverse events within 7 days. Main Results Eighty patients were randomized (41 prostacyclin, 39 placebo). The number of days alive without mechanical ventilation at 28-days was 16.0 days (SD 12) versus 5.0 days (SD 10), [95% CI -21.0 to 5.0], P=0.07) in the prostacyclin and the placebo groups, respectively. The 28-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (risk ratio 0.50 [95% CI 0.24 to 0.96] P=0.056). The incidence of serious adverse events within 7 days were 2.4% vs. 12,8% (risk ratio 0.19 [95% CI 0.001 to 1.11], P=0.10) in the prostacyclin and the placebo groups, respectively. Conclusions and relevance Prostacyclin were not associated with a significant reduction in the number of days alive and without mechanical ventilation within 28-days. The point estimates, however, favored the prostacyclin group in all analyses, including 28-day mortality, warranting further investigation in larger trials. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT04420741. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).