The time course and mechanism of vulnerability to ventricular fibrillation (VF) a 10-minute occlusion of the left anterior descending coronary artery and following its release were studied in 48 dogs. VF threshold was determined by inducing a sequence of three extrasystoles (sequential R/T pulsing). Within 1 minute of occlusion, the fibrillation current decreased to the level required for eliciting a propagated diastolic response. This state of enhanced vulnerability lasted for approximately 6 minutes, after which the VF threshold returned to preocclusion values. The vulnerability changes upon reperfusion, by comparison, occurred within seconds of release and persisted only transiently. Three minutes of occlusion was the minimal time which resulted in a reduction in VF threshold after release. Alpha and beta-adrenergic blockade with phentolamine and propranolol, respectively, prevented the decrease in VF threshold during occlusion but were without effect upon threshold changes during coronary artery release. Lidocaine failed to alter the pattern of vulnerability. It is concluded that adrenergic mechanisms play a key role in the increased susceptibility to VF associated with acute myocardial ischemia, whereas the changes in VF threshold following reperfusion may be due to washout products of cellular ischemia. These findings support the view that protection against VF during coronary artery occlusion and release may require different antiarrhythmic measures.