The effect of lidocaine on the ventricular fibrillation threshold was investigated in the anesthetized open-chest dog during paced supraventricular rhythm, during acute ligation of the anterior descending coronary artery, and during premature ventricular contractions. The minimum current (in milliamperes) required to induce ventricular fibrillation was determined by passing a train (100 Hz) of 10-14 constant-current pulses through ventricular epicardial electrodes during the vulnerable period of the cardiac cycle. Lidocaine was administered intravenously either as a sudden injection or as a “loading’ injection followed by a constant infusion. Following a single injection of 0.7 mg/kg the blood lidocaine decreased to half its original arterial concentration in 9 min. After the termination of a 50-60-min constant drip of 70 &mgr;g/kg/min which was preceded by a loading injection of 2 mg/kg, the blood lidocaine concentration fell to 50% of its original value in 31 min. Lidocaine at therapeutic blood levels (1.2-5.5 &mgr;g/ml) increased the fibrillation threshold during paced supraventricular rhythm and reversed the fall in fibrillation threshold accompanying acute myocardial ischemia and premature ventricular contractions. The present studies quantify the ability of lidocaine to reduce the vulnerability of the heart to fibrillation during supraventricular rhythm, acute ischemia, and premature ventricular beats and provide information concerning the metabolism of lidocaine in the anesthetized dog.