Researchers discovered a significant reduction in mean daily sequential organ failure assessment score in mechanically ventilated COVID-19 patients who received prostacyclin versus placebo in a pilot study. The effect on endothelial activation and damage biomarkers was investigated here. A post-doc analysis of a randomized controlled trial in mechanically ventilated adult patients with confirmed SARS-CoV-2 infection and plasma levels of soluble thrombomodulin (sTM) greater than 4 ng/mL. Patients were given either a prostacyclin infusion (1 ng/kg/min) or a placebo. Blood samples were taken at the beginning and after 24 hours. About 80 patients were randomly assigned (41 prostacyclins, 39 placeboes). The median changes in syndecan-1 plasma levels at 24 h were −3.95 (IQR: −21.1 to 2.71) ng/mL in the prostacyclin group vs 3.06 (IQR: −8.73 to 20.5) ng/mL in the placebo group (difference in medians: -7.01 [95% CI: −22.3 to −0.231] ng/mL, corresponding to −3% [95% CI: −11% to 0%], P=0.04)  sTM, PECAM-1, p-selectin, and CD40L plasma levels did not differ significantly between groups. In comparison to placebo, prostacyclin infusion resulted in a measurable decrease in endothelial glycocalyx shedding (syndecan-1) at 24 h, indicating a protective effect on the endothelium, which might be related to the observed decrease in organ failure.