A lidocaine bolus of 2 mg/kg has been shown to decrease the incidence of ventricular fibrillation in cardiac surgical patients during reperfusion following aortic cross-clamp release (CCR). In an effort to extend this effect into the immediate postoperative period, many centers routinely administer a prophylactic lidocaine infusion for the first 12 to 24 hours after surgery. Sequential total serum lidocaine levels were measured over 6 hours in 28 adult cardiac surgical patients without liver, kidney, or respiratory disease, and free serum lidocaine levels were measured in 15 of these patients. In addition, pharmacokinetic data were collected and analyzed in 8 of these patients. Each patient received a lidocaine bolus of 1.5 mg/kg and an infusion at 2 mg/min immediately before CCR. Serum levels were determined just before CCR, and at 10, 20, 30, 60, 120, 240, and 480 minutes after CCR. More than 50% of patients had subtherapeutic total serum lidocaine levels from 20 to 120 minutes after CCR, but free lidocaine levels remained within the therapeutic range. No patient showed malignant ventricular dysrhythmias during the study. The results suggest that (1) it may be misleading to estimate free lidocaine concentration based on total lidocaine levels; and (2) free drug is the moiety-responsible for lidocaine's antiarrhythmic effect.