Previous studies of hypercapnic ventilatory responses (HCVR) in human heart-lung transplant recipients (HLTX) have yielded conflicting results. We compared the HCVR of restricted transplant recipients (HLTX-R) to recipients with normal pulmonary function (HLTX-N), and normal controls (C). HLTX-R exhibited limited tidal volume responses, whereas their frequency responses were essentially identical to those of other subjects. Accordingly, HCVR of HLTX-R (1.45 ± 0.59 l · min-1 · Torr CO-1/2) were significantly depressed compared with both HLTX-N and C (2.90 ± 0.55 vs. 3.05 ± 1.23, respectively) (P < 0.02). Despite undoubtedly greater ventilatory impedances, airway (mouth) occlusion pressure responses (Pm0.1) during hypercarbia of HLTX-R (0.46 ± 0.28 cmH2O) were similar to those of C (0.43 ± 0.20) and paradoxically blunted compared with HLTX-N (0.83 ± 0.36) (P < 0.02). We conclude that pulmonary reflexes are superfluous for maintenance of HCVR in HLTX with normal respiratory mechanics, whereas the presence of moderate restriction results in profound depression of CO2 responses among these subjects.