Lack of synchrony between a patient and the mechanical ventilator occurs when the respiratory rhythm of the patient fails to entrain to machine inflations. Entrainment implies a resetting of the respiratory rhythm such that a fixed temporal relationship exists between the onset of inspiratory activity and the onset of a mechanical breath. We examined the entrainment response to mechanical ventilation of normal humans over a range of machine rates during wakefulness and during isocapnic and hypercapnic NREM sleep. Wakefulness facilitated 1:1 entrainment of the respiratory rhythm to the mechanical ventilator over a wider range of machine frequencies than during NREM sleep (p < 0.001); isocapnic and hypercapnic conditions did not differ (p = 0.95). To evaluate the Hering-Breuer reflexes in the resetting of the respiratory rhythm during sleep, we examined changes in neural inspiratory time (TI) as the relationship between inspiratory efforts and onset of machine inflations changed. As inspiratory efforts extended into the machine inflation cycle, neural TI shortened. We conclude that entrainment responses of normal humans to mechanical ventilation differ depending on state, but mild increases in respiratory drive caused by CO(2) stimulation do not affect these entrainment responses. Furthermore, the changes in neural TI are consistent with observations in animal studies in which Hering-Breuer reflexes mediated entrainment.