Passive lung inflation in humans causes reflex expiratory prolongation that is abolished by vagal blockade. We have studied two aspects of this classic Breuer-Hering reflex in humans: the effect of pulmonary denervation from bilateral lung transplantation, and the effect of alveolar hypocapnia. Lung inflations were performed in six normal subjects and four lung transplant patients during triazolam-induced sleep using a negative pressure body box. Lung inflation with isocapnic gas in normal subjects resulted in expiratory prolongation lasting up to 60 s and occurring at a volume threshold of 40 to 60% of inspiratory capacity (1.1 to 1.7 L). Expiratory prolongation increased in a graded fashion as volume of lung inflation increased. Inhibition of inspiration at any given inflation volume was prolonged by inflations with air as compared with inflations with isocapnic gas. In lung transplant patients lung inflations of up to 2 L caused no prolongation of expiration. We conclude that bilateral lung transplantation abolished expression of the reflex in humans, and that in normal intact humans the duration of expiratory prolongation with lung inflation is prolonged by alveolar hypocapnia.