Background It had been shown that High-flow nasal cannula (HFNC) is an effective initial support strategy for patients with acute respiratory failure. However, the efficacy of HFNC for patients with COVID-19 has not been established. This study was performed to assess the efficacy of HFNC for patients with COVID-19 and describe early predictors of HFNC treatment success in order to develop a prediction tool that accurately identifies the need for upgrade respiratory support therapy. Methods We retrospectively reviewed the medical records of patients with COVID-19 treated by HFNC in respiratory wards of 2 hospitals in Wuhan between 1 January and 1 March 2020. Overall clinical outcomes, the success rate of HFNC strategy and related respiratory variables were evaluated. Results A total of 105 patients were analyzed. Of these, 65 patients (61.9%) showed improved oxygenation and were successfully withdrawn from HFNC. The PaO2/FiO(2) ratio, SpO(2)/FiO(2) ratio and ROX index (SpO(2)/FiO(2)*RR) at 6h, 12h and 24h of HFNC initiation were closely related to the prognosis. The ROX index after 6h of HFNC initiation (AUROC, 0.798) had good predictive capacity for outcomes of HFNC. In the multivariate logistic regression analysis, young age, gender of female, and lower SOFA score all have predictive value, while a ROX index greater than 5.55 at 6 h after initiation was significantly associated with HFNC success (OR, 17.821; 95% CI, 3.741-84.903 p<0.001). Conclusions Our study indicated that HFNC was an effective way of respiratory support in the treatment of COVID-19 patients. The ROX index after 6h after initiating HFNC had good predictive capacity for HFNC outcomes.