To evaluate the effects of chronic pulmonary denervation on ventilatory control, we compared the hypercarbic ventilatory responses (HCVR) of 12 human heart-lung transplant recipients (HL) and 24 normal control subjects (C). The six male HL were subsequently compared with eight male heart transplant recipients (H), as well as the 12 male C. All subjects had normal spirometry, but lung volumes of both transplant groups were somewhat less than those of C. The HCVR of HL and C were indistinguishable (2.68 ± 0.28 versus 2.71 ± 0.22 L/min/mm Hg, respectively). The increment of mouth occlusion pressure (ΔPm0.1/ΔCO2), however, was markedly greater in HL (p << 0.01). The three male groups also had equivalent HCVR, and again, the HL had an increased ΔPm0.1/ΔCO2. HL men exhibited larger increments of VT and decreased frequency responses during CO2 rebreathing than did male C and H, although these differences were statistically significant only in the comparison between the transplant groups. We conclude that HL with normal spirometry have appropriate HCVR, despite pulmonary denervation. Pm0.1 responses of these subjects are increased, however, reflecting either a compensatory response to greater respiratory impedances or an occult alteration of ventilatory mechanics. Moreover, compared with subjects with similar pulmonary function, e.g., heart transplant recipients, the breathing pattern of HL during progressive hypercarbia is consistent with the absence of vagal-mediated inflation inhibition.