INTRODUCTION Limited evidence exists regarding use of inhaled nitric oxide (iNO) in spontaneously breathing patients. We evaluated the effectiveness of continuous iNO via high-flow nasal cannula (HFNC) in COVID-19 respiratory failure. METHODS We performed a multicenter cohort study of patients with respiratory failure from COVID-19 managed with HFNC. Patients were stratified by administration of iNO via HFNC. Regression analysis was used to compare the need for mechanical ventilation and secondary endpoints including hospital mortality, length of stay, acute kidney injury, need for renal replacement therapy, and need for extracorporeal life support. RESULTS A total of 272 patients were identified and 66 (24.3%) of these patients received iNO via HFNC for a median of 88 h (interquartile range: 44, 135). After 12 h of iNO, supplemental oxygen requirement was unchanged or increased in 52.7% of patients. Twenty-nine (43.9%) patients treated with iNO compared to 79 (38.3%) patients without iNO therapy required endotracheal intubation (P = .47). After multivariable adjustment, there was no difference in need for mechanical ventilation between groups (odds ratio: 1.53; 95% confidence interval CI: 0.74-3.17), however, iNO administration was associated with longer hospital length of stay (incidence rate ratio: 1.41; 95% CI: 1.31-1.51). No difference was found for mortality, acute kidney injury, need for renal replacement therapy, or need for extracorporeal life support. CONCLUSION In patients with COVID-19 respiratory failure, iNO delivered via HFNC did not reduce oxygen requirements in the majority of patients or improve clinical outcomes. Given the observed association with increased length of stay, judicious selection of those likely to benefit from this therapy is warranted.