Lidocaine directly affects conduction and refractoriness of ventricular myocardium, and may also indirectly affect these electrophysiologic properties by inhibition of cardiac sympathetic nerve traffic. Both effects may play important roles in preventing ventricular arrhythmias in humans. To determine if lidocaine has a direct effect on sympathetic nerve activity, the effects of a 100 mg lidocaine bolus followed by a 2 mg/min infusion of lidocaine on muscle sympathetic nerve activity was assessed in seven patients during programmed ventricular stimulation with single extrastimuli (premature ventricular contractions [PVCs]) in sinus rhythm, and in seven patients during induced hemodynamically stable monomorphic ventricular tachycardia. During single extrastimuli, the mean (± SEM) area of PVC-associated bursts of sympathetic nerve activity was unaffected by lidocaine (1101 ± 16 units pre-lidocaine versus 1075 ± 19 units following lidocaine; p = 0.30). Likewise, the transient decrease in blood pressure with induced PVCs was similar before and after lidocaine infusion (p = 0.46). In seven patients with induced monomorphic ventricular tachycardia, tachycardia cycle length did not change after the lidocaine bolus (393 ± 18 versus 399 ± 17 msec; p = 0.34) but increased during lidocaine maintenance infusion (428 ± 17 msec; p = 0.01). After induction of ventricular tachycardia, systolic pressure decreased from 150 ± 6 to 117 ± 9 mm Hg at 1 minute of tachycardia, to 109 ± 6 mm Hg during the lidocaine bolus, and rebounded to 126 ± 8 mm Hg during the lidocaine maintenance infusion (p = 0.04, bolus versus infusion). Sympathetic nerve activity (units/5 seconds) increased from 817 ± 123 to 1775 ± 274 units during ventricular tachycardia (p < 0.01 versus baseline) to 1798 ± 453 units after lidocaine bolus and to 1460 ± 380 units during the lidocaine infusion (p = 0.04 versus pre-lidocaine). The change in blood pressure during ventricular tachycardia with the lidocaine maintenance infusion correlated inversely with the change in sympathetic nerve activity (r = -0.69, p = 0.002). Lidocaine appears to reduce sympathetic nerve activity indirectly by slowing ventricular tachycardia cycle length, which results in increased blood pressure during tachycardia. These data suggest that therapeutic doses of lidocaine do not directly alter sympathetic nerve activity in humans.