Respiratory muscle weakness can impair cough function, leading to lower respiratory tract infections. These infections are an important contributor to morbidity and mortality in patients with neuromuscular disease. Mechanical insufflation-exsufflation (MIE) is used to augment cough function in these patients. Although MIE is widely used, there are few data to advise on the optimal technique. Since the introduction of MIE, the recommended pressures to be delivered have increased. There are concerns regarding the use of higher pressures and their potential to cause lung derecruitment and upper airway closure. What is the impact of high-pressure MIE (HP-MIE) on lung recruitment, respiratory drive, upper airway flow, and patient comfort, compared with low-pressure MIE (LP-MIE), in patients with respiratory muscle weakness? Clinically stable patients using domiciliary MIE with respiratory muscle weakness secondary to Duchenne muscle dystrophy, spinal cord injury, or long-term tracheostomy ventilation received LP-MIE (30/-30cm H2O) and HP-MIE (60/-60cm H2O) in a random sequence. Lung recruitment, neural respiratory drive, and cough peak expiratory flow were measured throughout, and patients reported comfort and breathlessness following each intervention. A total of 29 patients (10 with Duchenne muscle dystrophy, eight with spinal cord injury, and 11 with long-term tracheostomy ventilation) were included in this study. HP-MIE augmented cough peak expiratory flow compared with LP-MIE (mean cough peak expiratory flow HP-MIE 228 ± 81 L/min vsLP-MIE 179 ± 67 L/min; P= .0001) without any significant change in lung recruitment, neural respiratory drive, or patient-reported breathlessness. However, in patients with more pronounced respiratory muscle weakness, HP-MIE resulted in an increased rate of upper airway closure and patient discomfort that may have an impact on clinical efficacy. HP-MIE did not lead to lung derecruitment or breathlessness compared with LP-MIE. However, it was poorly tolerated in individuals with advanced respiratory muscle weakness. HP-MIE generates more upper airway closure than LP-MIE, which may be missed if cough peak expiratory flow is used as the sole titration target. ClinicalTrials.gov; No.: NCT02753959; URL: www. gov.