In contrast to limb muscles, the usual response of human inspiratory muscles to sudden loading consists of an initial marked reduction of electromyographic activity (EMG) followed by a subsequent increase in EMG. To determine definitively whether pulmonary receptors are necessary for this short-latency reflex inhibition produced by airway occlusion, we studied five subjects with complete pulmonary denervation due to bilateral transplantation of the lungs and five matched control subjects. Subjects with pulmonary denervation were studied between 10 and 50 days after transplantation (median 21 days). Brief airway occlusion during inspiration (i.e., loading; duration 250 ms) produced short-latency reduction in EMG in the inspiratory muscles of all subjects with acute pulmonary denervation (scalenes and parasternal intercostal muscles; mean onset of inhibition 27 and 29 ms, respectively). The ongoing EMG was reduced by an average of 50% in scalenes and 36% in parasternal intercostal muscles. The size and the magnitude of the initial response did not differ significantly from those in control subjects. After the occlusion (i.e., unloading), activity of the inspiratory muscles was transiently reduced in control subjects and patients after bilateral lung transplantation. Given that the initial responses to airway loading and unloading were preserved after bilateral lung transplantation, we conclude that these reflex responses are not critically dependent on the discharge of intrapulmonary receptors. The results support the view that the short-latency inspiratory responses to loading and unloading can be mediated by inspiratory muscle afferents. They suggest a functionally different organization of the reflex pathways for inspiratory compared with limb muscles.