A large heart rate (HR) increase at the onset of exercise has been linked to an increased risk for adverse cardiovascular events, including cardiac death. However, the relationship between changes in cardiac autonomic regulation induced by exercise onset and the confirmed susceptibility to ventricular fibrillation (VF) has not been established. Therefore, a retrospective analysis of the HR response to exercise onset was made in mongrel dogs with healed myocardial infarctions that were either susceptible (S, n = 131) or resistant (R, n = 114) to VF (induced by a 2-min occlusion of the left circumflex artery during the last minute of exercise). The ECG was recorded, and time series analysis of HR variability (vagal activity index, the 0.24–1.04-Hz frequency component of R-R interval variability) was measured before and 30, 60, and 120 s after the onset of exercise (treadmill running). Exercise elicited significantly (ANOVA, P < 0.0001) greater increases in HR in susceptible dogs at all three times (e.g., at 60 s: R, 46.8 � 2.3 vs. S, 57.1 � 2.2 beats/min). However, the vagal activity index decreased to a similar extent in both groups of dogs (at 60 s: R, −2.8 � 0.1 vs. S, −3.0 � 0.2 ln ms²). β-Adrenoceptor blockade (BB, propranolol 1.0 mg/kg iv) reduced the HR increase and eliminated the differences noted between the groups [at 60 s: R (n = 26), 40.4 � 3.2 vs. S (n = 31), 37.5 � 2.4 beats/min]. After BB, exercise once again elicited similar declines in vagal activity in both groups (at 60 s: R, −3.6 � 0.5 vs. S, −3.2 � 0.4 ln ms²). When considered together, these data suggest that at the onset of exercise HR increases to a greater extent in animals prone to VF compared with dogs resistant to this malignant arrhythmia due to an enhanced cardiac sympathetic activation in the susceptible dogs.