Objectives This study examined the hypothesis that the sympathomimetic activity of ephedrine increases the risk of lethal arrhythmias. Background The sympathomimetic amine, ephedrine, is used to augment physical performance and as a weight loss aid, but little is known about the cardiovascular consequences in individuals with ischemic heart disease. Methods Fifteen dogs at low risk for ventricular fibrillation (VF) during exercise and transient myocardial ischemia 30 days after a small anterior myocardial infarction were retested after five days of ephedrine use (Xenadrine, 0.4 mg/kg/day orally). To assess the effects of ephedrine on cardiac autonomic control, baroreceptor reflex sensitivity (BRS), heart rate (HR) variability, HR response to acute myocardial ischemia, and resting catecholamines were measured before and after ephedrine. Dogs were used as their own control when possible. Results Nine of 15 animals had increased ventricular arrhythmias during ephedrine treatment (p = 0.01) and four had VF. Three dogs that had VF could not be resuscitated. Five animals with increased arrhythmias during ephedrine treatment had none during a third exercise and ischemia test after drug washout. Heart rates were higher after 30 s of myocardial ischemia during ephedrine treatment (204 ± 25 beats/min no drug vs. 218 ± 26 beats/min with ephedrine, p = 0.03). All plasma catecholamines increased after ephedrine administration. No changes in BRS, HR variability, or exercise HR were noted. Conclusions Ephedrine increases ischemia-dependent arrhythmias at doses recommended in over-the-counter preparations. Increased arrhythmia risk was associated with augmented ischemia-dependent sympathetic reflex activation.