Background Early prediction of non-invasive ventilation failure by using clinical parameters and scoring systems is a promising strategy for reducing mortality in acute exacerbation of chronic obstructive pulmonary disease patients. Our aim was to assess predictors of non-invasive ventilation failure in acute exacerbation of chronic obstructive pulmonary disease and the prognostic role of mid-regional proadrenomedullin. Results Forty-five patients were enrolled, comprising thirty-six males and nine females with mean age 63.4 ± 9.22 years. Mid-regional proadrenomedullin could not predict non-invasive ventilation outcome, while acute physiology and chronic health evaluation score, blood pH, arterial carbon dioxide and platelet count had predictive value. Conclusion Prediction of non-invasive ventilation outcome in acute exacerbation of chronic obstructive pulmonary disease patients is multifactorial and mid-regional proadrenomedullin alone could not predict this outcome.