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Background Critically ill coronavirus disease 2019 (COVID-19) patients may suffer persistent systemic inflammation and multiple organ failure, leading to a poor prognosis. Research question To examine the relevance of the novel inflammatory factor heparin-binding protein (HBP) in critically ill COVID-19 patients, and evaluate the correlation of the biomarker with disease progression. Study design and methods 18 critically ill COVID-19 patients who suffered from respiratory failure and sepsis, including 12 cases who experienced a rapidly deteriorating clinical condition and six cases without deterioration, were investigated. They were compared with 15 age- and sex- matched COVID-19-negative patients with respiratory failure. Clinical data were collected and HBP levels were investigated. Results HBP was significantly increased in critically ill COVID-19 patients following disease aggravation and tracked with disease progression. HBP elevation preceded the clinical manifestations for up to 5 days and was closely correlated with patients’ pulmonary ventilation and perfusion status. Interpretation HBP levels are associated with COVID-19 disease progression in critically ill patients. As a potential mediator of disease aggravation and multiple organ injuries that are triggered by continuing inflammation and oxygen deficits, HBP warrants further study as a disease biomarker and potential therapeutic target.