The authors studied the effect of lidocaine infusion on the ventilatory response to isocapnic hypoxia in nine healthy male subjects. Lidocaine infusion (serum concentration 3.6 ± 0.1 μg/ml) was associated with a decrease in the shape factor, “A,” of the hypoxic ventilatory response in eight of our nine subjects (P< 0.02). Overall, “A” decreased from 419 ± 102 1·min−1·mmHg before lidocaine to 335 ± 77 1·min−1·mmHg during lidocaine infusion (&OV0335; ± SEM, N = 9). The authors conclude that despite significant intersubject variability, clinically useful serum lidocaine concentrations depress hypoxic ventilatory drive. Patients with carbon dioxide retention, whose resting ventilation depends on hypoxic drive, may be at risk of ventilatory failure when lidocaine is administered for arrhythmia control or regional anesthesia.