During hypercapnia-induced hyperventilation, obese patients with a prior history of alveolar hypoventilation appear to have significantly more blunted ventilatory response than simply obese patients who never retained carbon dioxide. In addition, these patients with former obesity-hypoventilation syndrome have decreased neuromuscular responses as measured by way of the mouth occlusion technique when compared with either the patients with simple obesity or normal subjects. The patients with simple obesity appear to have augmented responses in comparison with normal subjects. Simple mechanical considerations and baseline breathing variables failed to distinguish the simple obesity group from the group with former obesity-hypoventilation syndrome. Thus, the decreased neuromuscular responsiveness to carbon dioxide (mouth-occlusion pressure/end-tidal carbon dioxide pressure) among the group with former obesity-hypoventilation syndrome when compared with that in the group with simple obesity is a consequence of a blunted neural (central) drive, and not due to any apparent worse mechanical limitations. The augmented mouth-occlusion pressure/end-tidal carbon dioxide pressure and increased integrated, rectified electromyographic signal of the diaphragm found in the group with simple obesity presumably reflect their attempt to maintain ventilatory homeostasis in the presence of severe respiratory loads. Neuromechanical coupling values, as reflected in the integrated electromyographic signal of the diaphragm versus transdiaphragmatic pressure and mouth-occlusion pressure versus mean inspiratory flow, are identical in the two groups. On the basis of these studies, it would appear that although mechanical loads put all obese patients at a disadvantage, the addition of an acute extra load on the respiratory system produces the obesity-hypoventilation syndrome in those obese persons who have truly blunted central hypercapnic responses.