Acute respiratory failure is a life-threatening condition characterized by an inability to maintain normal levels of oxygen and/or carbon dioxide gas exchange due to dysfunction of the respiratory system. In its most basic sense, the respiratory system comprises a gas exchanging organ (lung) and a ventilatory pump (respiratory muscles and controllers, chest wall). Respiratory failure is classified based on failure of one or both of these elements, as well as the timing of such failure. Acute respiratory failure develops over minutes to several days. Respiratory failure is deemed chronic when derangements occur over several days or longer. Acute-on-chronic respiratory failure occurs when a patient with chronic respiratory failure suffers an acute deterioration in gas exchange; this is most commonly seen in patients with severe chronic obstructive pulmonary disease (COPD). The epidemiology of acute respiratory failure is not fully known. In the United States, millions of patients are admitted to the intensive care unit (ICU) each year, and acute respiratory failure is the most common cause. Acute respiratory failure is severe enough to require life support with invasive mechanical ventilation for approximately 800,000 Americans a year, a high proportion of whom do not survive the episode. Epidemiological studies have estimated the annual incidence of acute respiratory failure to be between 77.6 and 430 patients per 100,000. The estimated health care costs related to critical care are approximately 0.7 percent of the annual gross domestic product, and the human and financial costs are only expected to increase with an aging population. The literature supporting the use of NPPV for respiratory failure in the acute-care setting has evolved over the last two decades. Although there have been some exceptions, such as a 2010 meta-analysis examining NPPV in acute respiratory failure of multiple causes, the use of NPPV has been most extensively studied in patients with acute respiratory failure due to COPD and congestive heart failure. In addition to these two well-studied uses, there is increasing interest in determining if NPPV is beneficial for other causes of acute respiratory failure (e.g., asthma) or can shorten the duration of invasive mechanical ventilation, either as a method to facilitate early extubation or to prevent extubation failure in high-risk groups. Further, there is uncertainty about whether the beneficial effects demonstrated in randomized controlled trials (RCTs) are replicated in real-world settings where training, experience, organizational factors, and patient factors may differ substantially. Additionally, it is uncertain whether the effects of NPPV vary by clinician experience and training, the use of protocols, the setting in which NPPV initiation is applied, or by specific patient characteristics. This comparative effectiveness review (CER) was commissioned by the Agency for Healthcare Research and Quality (AHRQ) to evaluate the evidence for NPPV versus other typical treatments for acute respiratory failure. We conducted a systematic review that is inclusive of all major causes of acute respiratory failure and includes studies of NPPV used for weaning from invasive ventilation. We anticipate that clinicians involved in medical and surgical critical care medicine, emergency medicine, and anesthesiology, along with developers of clinical practice guidelines, will be the primary audience for this report.