<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>High flow nasal cannula (HFNC) therapy is widely employed in acute hypoxemic respiratory failure (AHRF) patients. However, the techniques for predicting HFNC outcome remain scarce.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>PubMed, EMBASE, and Cochrane Library were searched until April 20, 2021. We included the studies that evaluated the potential predictive value of ROX (respiratory rate-oxygenation) index for HFNC outcome. This meta-analysis determined sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic score, diagnostic odds ratio (DOR), and pooled area under the summary receiver operating characteristic (SROC) curve.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We assessed nine studies with 1933 patients, of which 745 patients experienced HFNC failure. This meta-analysis found that sensitivity, specificity, PLR, NLR, diagnostic score, and DOR of ROX index in predicting HFNC failure were 0.67 (95% CI 0.57–0.76), 0.72 (95% CI 0.65–0.78), 2.4 (95% CI 2.0–2.8), 0.46 (95% CI 0.37–0.58), 1.65(95% CI 1.37–1.93), and 5.0 (95% CI 4.0–7.0), respectively. In addition, SROC was 0.75 (95% CI 0.71–0.79). Besides, our subgroup analyses revealed that ROX index had higher sensitivity and specificity for predicting HFNC failure in COVID-19 patients, use the cut-off value > 5, and the acquisition time of other times after receiving HFNC had a greater sensitivity and specificity when compared to 6 h.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>This study demonstrated that ROX index could function as a novel potential marker to identify patients with a higher risk of HFNC failure. However, the prediction efficiency was moderate, and additional research is required to determine the optimal cut-off value and propel acquisition time of ROX index in the future.</jats:p> <jats:p>PROSPERO registration number: CRD42021240607.</jats:p> </jats:sec>