Background: Several reports suggest endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase (HPSE) contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that HPSE may be inhibited by the use of LMWH. Methods: Heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n=10) and COVID-19 patients (n=48). Findings: Heparanase activity and heparan sulfate levels were significantly elevated in plasma of COVID-19 patients. There was an association between heparanase activity and disease severity including the need for intensive care and mechanical ventilation, lactate dehydrogenase levels and creatinine levels. Use of prophylactic low molecular weight heparin in non-ICU patients was associated with a reduced HPSE activity. Interpretation: Prophylactic doses of low molecular weight heparin reduces heparanase activity in COVID-19. In addition to HPSE inhibition, low molecular weight heparin contributes to anti-coagulation and may exert anti-inflammatory effects. Since there is no other clinically applied heparanase inhibitor currently available, treatment of COVID-19 patients with low molecular weight heparins should be explored. Funding: This study was financially supported by the Radboudumc PhD fellow program, consortium grant LSHM16058-SGF (GLYCOTREAT; a collaborative project financed by the PPP allowance made available by Top Sector Life Sciences & Health to the Dutch Kidney Foundation to stimulate public-private partnerships), ERC Advanced grant (#833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research.