Objective: To test the hypothesis that either decreased ventilatory drive or decreased CO2 responsiveness accounts for the hypoventilation observed in patients during acute ventilatory failure from myasthenia gravis or Guillain-Barré syndrome. Design: Prospective, consecutive case series evaluating trials of ventilatory muscle performance, ventilatory drive, and CO2 response in patients during recovery from ventilatory failure until they were weaned from mechanical ventilation. Setting: Neurosciences critical care unit in a university hospital. Patients: Seven intubated, mechanically ventilated patients with myasthenia gravis or Guillain-Barré syndrome. Interventions: Patients repeatedly performed mechanically unsupported, spontaneous breathing trials to the limits of endurance. After spontaneous breathing trials, patients underwent CO2 rebreathing studies. Measurements and Main Results: Seventy-three breathing trials were performed in three patients with Guillain-Barré syndrome and four patients with myasthenia gravis. Patients were unable to sustain spontaneous ventilation in 55 trials averaging 27 ± 5 mins. In these trials, significant increases occurred in mean end-tidal CO2 (41 ± 1 to 44 ± 1 torr [5.6 ± 0.1 to 6.0 ± 0.1 kPa]) and respiratory rate (31 ± 1 to 35 ± 1 breaths/min, p < .01). Ventilatory drive (as measured by airway occlusion pressure for 100 msecs) increased significantly p < .01 from 3.7 ± 0.3 to 4.9 ± 0.3 cm H2O. The response of airway occlusion pressure to CO2 rebreathing after these trials was 0.33 ± 0.07 cm H2O/sec/mm Hg, while the minute ventilation response to CO2 rebreathing was only 0.30 ± 0.06 L/min/mm Hg. Conclusions: These results suggest that ventilatory drive increases during acute hypoventilation, and the ventilatory drive response to CO2 remains intact, even when the minute ventilation response to CO2 is poor. Therefore, a decrease in ventilatory drive or CO2 response is unlikely to account for hypoventilation during ventilatory failure in patients with myasthenia gravis or Guillain-Barré syndrome. (Crit Care Med 1993; 21:1717–1726)