The day-to-day variations in epicardial defibrillation threshold (DFT) were examined in closed-chest, unanesthetized dogs. In 11 animals, DFT decreased from 15.8 ± 2.1 J (mean SE) at the beginning of the study (day 1), to 7.4 + 1.7 J on day 2 (p < .0001). DFT measured daily for 5 consecutive days in seven dogs decreased from 22.1 + 3.1 J on day 1 to 9.3 + 2.3 J on day 2 (p < .01) and remained stable from day 2 to day 5. Transcardiac impedance, measured in six dogs, decreased from 112 + 6 Q on day 1 to 100 + 6 Q on day 2 (p = NS). Propranolol given on day 2 in 14 dogs increased DFT from 12.0 + 2.2 to 18.0 ± 3.1 J (p < .05). The effects on DFT of sequential administration of isoproterenol and propranolol were examined in 10 dogs. Isoproterenol decreased DFT from 10. O + 1. 9 to 5.5 + 1. 5 J when given before propranolol (p < .001, n = 10), and from 1 1. 7 ± 3.0 to 9.7 + 3.1 J when given after propranolol (p < .05, n = 9). Propranolol increased DFT from 10.6 + 3.0 to 14.6 + 3.9 J when given before isoproterenol (p < .02, n = 9), and from 10.7 + 1.4to 14.4 + 1.5 J when given after isoproterenol (p < .01, n = 10). These experiments demonstrate a sustained cardiac effect of epicardial defibrillation reflected by a decrease in DFT that is partially reversible by propranolol. A similar decrease was produced by /3-adrenergic stimulation, an effect that was partially blocked by propranolol. Thus, variations in the autonomic state of the heart may be an important modulator of cardiac DFT. These findings, however, are experimental, and do not support the use of isoproterenol alone in traditional clinical defibrillation.