Human consumption of ephedrine and caffeine in dietary supplements has been associated with a number of adverse effects including changes in the electrocardiogram (ECG), myocardial infarction, hyperthermia, and in rare instances, death. The purpose of this study was to investigate the potential mechanisms associated with the cardiotoxicity of combined ephedrine and caffeine ingestion. Seven and 14 week old Fischer 344 rats treated with ephedrine in combination with caffeine exhibited increases in heart rate (HR), temperature and QTc interval. Of the 14 week old rats treated with 25 mg/kg ephedrine plus 30 mg/kg caffeine, 57% died within 3-5 hours of treatment, while none of the similarly treated 7 week old rats nor any of the rats treated with vehicle died. One hour after treatment with this dose of ephedrine plus caffeine, 14 week old rats treated with this dose exhibited a larger increase in HR (as % increase over baseline) than 7 week old rats. Furthermore, the 14 week old rats that died had a higher HR and temperature than the 14 week old rats that lived. Histopathological studies suggested interstitial hemorrhage and myofiber necrosis in the 14 week old rats treated with the highest concentration of ephedrine and caffeine. This study showed enhanced susceptibility to ephedrine plus caffeine in 14 week old rats compared to 7 week old rats. The greater mortality in the 14 week old rats was associated with increases in body temperature, heart rate and myocardial necrosis.