Thrombocytopenia, elevated levels of IL-6 at HFNC initiation, and an ROX index <5.31 within the first 4 h of HFNC therapy were independent predictors of HFNC failure, and the risk-stratification model on the basis of the four parameters, has a strong predictive ability for the need for MV in COVID-19 patients with HFNC therapy and can further classify the risk of HFNC failure. Here, IL6 is linked to Thrombocytopenia.