Animal and human studies have suggested that higher doses of epinephrine than currently recommended may improve resuscitation rates after prolonged cardiac arrest. Because of our failure to resuscitate four patients with the standard American Heart Association protocol for cardiac arrest, we used a larger dose of epinephrine in an attempt to enhance resuscitative efforts. All patients required CPR and had nonperfusing rhythms for at least 20 minutes. The four patients received from 0.12 to 0.22 mg/kg epinephrine. Within five minutes of high-dose epinephrine, all four patients developed perfusing rhythms with maximum systolic blood pressures ranging from 134 to 220 mm Hg. Cardiac dysrhythmias did not occur after these doses of epinephrine. Only one of four patients had ECG evidence of an acute myocardial infarction. In this patient, the history suggested that the myocardial infarction was a primary event, not the consequence of epinephrine. All four patients sustained severe brain injury leading to their demise. This injury was probably due to prolonged cardiopulmonary arrest and global brain ischemia. Pharmacologic and potential pathophysiologic mechanisms of high-dose epinephrine are reviewed.