BACKGROUND: Currently, there is a deficiency in nomograms specifically designed for predicting the failure of high-flow nasal cannula (HFNC) oxygen therapy in patients with hypercapnic acute respiratory failure (hypercapnic ARF). The aim of this retrospective study is to develop and evaluate a nomogram that assesses the risk of HFNC failure in this patient population. METHODS: Patients with ARF and hypercapnia (PaCO RESULTS: A total of 189 patients were included in the analysis, comprising 128 patients in the HFNC success group and 61 in the HFNC failure group. Multivariate logistic regression identified blood urea nitrogen, calcium, sepsis, and the respiratory rate oxygenation index (ROX) after 4 h of oxygen therapy as independent prognostic factors for HFNC failure. The nomogram exhibited superior performance compared to the Sequential Organ Failure Assessment score (P = 0.011) and the 4-h ROX index (P = 0.001). Additionally, the calibration curve demonstrated satisfactory predictive accuracy, while DCA highlighted the clinical utility of the nomogram. CONCLUSION: Key demographic and laboratory parameters associated with the failure of HFNC in patients with hypercapnic ARF have been identified. These parameters were used to develop a precise and user-friendly nomogram, which could serve as an effective clinical tool for clinicians.