This retrospective cohort study on COVID-19 patients with AHRF showed that age older than 60 years, thrombocytopenia, elevated levels of IL-6 at HFNC initiation, and an ROX index <5.31 within the first 4 h of HFNC therapy initiation were independent predictors of HFNC failure. The gene discussed is IL6; the disease is COVID-19.