Background Heparin-binding protein (HBP) is an inflammatory protein released by activated polymorphonuclear white cells. It has been suggested as a predictor of sepsis progression and organ dysfunction and plays a role in the pathophysiology of endothelial dysfunction. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor with pro-inflammatory effects, and high levels are found in patients with sepsis and acute respiratory distress syndrome. We investigated HBP and ET-1 plasma levels in critical COVID-19 disease with the aim of evaluating whether they were associated with 60-day mortality or the need for invasive mechanical ventilation (IMV). These levels were compared with those of a cohort of post-trauma intensive care unit (ICU) patients.Methods We included 96 patients with critical COVID-19 disease in 2020 and ten post-trauma ICU patients. Blood samples were collected at ICU admission, and plasma levels of HBP and ET-1 were measured. Clinical and laboratory data were collected until ICU discharge or death.Results In COVID-19 patients, plasma levels of HBP were markedly increased, with a median level of 150 ng/ml (IQR 47–299), compared to 13.3 ng/ml (IQR 8.8–62.1), p < 0.0001 in the trauma ICU patients. There was no association between HBP levels and 60-day mortality or need for IMV. The levels of ET-1 were 1.6 pg/ml (IQR 1.2–1.9) in the COVID-19 cohort and 2.0 pg/ml (IQR 1.2–2.8), p = 0.25 in the trauma ICU cohort. COVID-19 patients requiring IMV hade higher ET-1 levels than those who did not require such treatment; however, no association was found in a logistic regression model when adjusted for age, sex and body mass index. There was no correlation between plasma HBP and ET-1 levels. Inflammatory parameters such as C-reactive protein, procalcitonin, ferritin, and interleukin-6, were elevated but did not distinguish survivors from non-survivors.Conclusion While HBP levels are markedly elevated in critical COVID-19, they do not predict outcomes at ICU admission. ET-1 levels were also not linked to mortality or the need for IMV.