Many patients with severe chronic obstructive pulmonary disease (COPD) report unpleasant respiratory sensation at rest, further amplified by adoption of supine position (orthopnoea). The mechanisms of this acute symptomatic deterioration are poorly understood.16 patients with advanced COPD and history of orthopnoea and 16 age- and sex-matched healthy controls (CTRL) underwent pulmonary function tests and detailed sensory-mechanical measurements including inspiratory neural drive (IND, diaphragm electromyography), oesophageal and gastric pressures in sitting and supine positions.Patients had severe airflow obstruction (FEV1: 40±18%predicted) and lung hyperinflation. Regardless of the position, patients had lower inspiratory capacity (IC) and higher IND for a given tidal volume (i.e. greater neuromechanical dissociation (NMD)), higher intensity of breathing discomfort, minute ventilation (⩒E) and breathing frequency (Fb) compared with CTRL (all p<0.05). In supine position in CTRL (versus sitting erect): IC increased (by 0.48L) with a small drop in ⩒E mainly due to reduced Fb (all p<0.05). By contrast, patients' IC remained unaltered, but dynamic lung compliance decreased (p<0.05) in the supine position. Breathing discomfort, inspiratory work of breathing, inspiratory effort, IND, NMD and neuro-ventilatory uncoupling all increased in COPD in the supine position (p<0.05), but not in CTRL. Orthopnoea was associated with acute changes in IND (r=0.65, p=0.01), neuro-ventilatory uncoupling (r=0.76, p=0.001) and NMD (r=0.73, p=0.002).In COPD, onset of orthopnoea coincided with an abrupt increase in elastic loading of the inspiratory muscles in recumbency in association with increased IND and greater neuromechanical dissociation of the respiratory system.