Objective To analyze the risk factors of treatment failure by noninvasive positive pressure ventilation (NPPV) in patients with acute respiratory failure (ARF) due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD), and explore the best time that NPPV be replaced by invasive ventilation when NPPV failure occurs. Methods The data of patients with ARF due to AECOPD who were treated with NPPV from January 2013 to December 2015 were retrospectively collected. The patients were divided into two groups: the NPPV success group and the NPPV failure group (individuals who required endotracheal intubation or tracheotomy at any time). The Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ score was analyzed; the Glasgow Coma Scale score, respiratory rate (RR), pH value, partial pressure of oxygen (PaO2), PaO2/fraction of inspired oxygen (FiO2) ratio, and partial pressure of carbon dioxide were also analyzed at admission, after 2 hours of NPPV, and after 24 hours of NPPV. Results A total of 185 patients with ARF due to AECOPD were included. NPPV failed in 35.1% of the patients (65/185). Multivariate analysis identified the following factors to be independently associated with NPPV failure: APACHEⅡscore≥30 [odds ratio (OR)=20.603, 95% confidence interval (CI) (5.309, 80.525), P<0.001], RR at admission≥35 per minute [OR=3.723, 95%CI (1.197, 11.037), P=0.020], pH value after 2 hours of NPPV<7.25 [OR=2.517, 95%CI (0.905, 7.028), P=0.070], PaO2 after 2 hours of NPPV<60 mm Hg (1 mm Hg=0.133 kPa) [OR=3.915, 95%CI (1.374, 11.508), P=0.010], and PaO2/FiO2 after 2 hours of NPPV<200 mm Hg [OR=4.024, 95%CI (1.542, 11.004), P=0.010]. Conclusion When patients with ARF due to AECOPD have a higher severity score, have a rapid RR at admission, or fail to improve in terms of pH and oxygenation after 2 hours of NPPV, the risk of NPPV failure is higher.