The hyperthyroid heart has a greater oxygen demand due to its enhanced contractile state and higher basal metabolic rate. Consequently, it may be more sensitive to conditions of decreased oxygen supply or increased oxygen use. We, therefore, investigated the effect of a restricted oxygen supply (hypoxia) and enhanced oxygen demand (catecholamine stimulation) on cardiac function in the isolated working hyperthyroid heart. Hypoxia was induced by substituting 20% of the oxygen in the perfusate with nitrogen, while catecholamine stimulation was with isoproterenol. Hypoxia caused a 37% drop in cardiac output in the hyperthyroid heart and a 10% decrease in euthyroid hearts. In response to isoproterenol, a dose-dependent increase in heart rate was found in both groups which was greatly augmented in the hyperthyroid hearts by hypoxia. With isoproterenol stimulation under normoxic conditions, euthyroid hearts showed a moderate increase in contractile performance (cardiac output and dP/dtmax), while in hyperthyroid hearts contractile performance declined. Hypoxia exacerbated the decrease in function of the hyperthyroid heart. In conclusion, our results indicate that the hyperthyroid heart is very sensitive to imbalances in the myocardial oxygen supply/demand ratio, especially when demand is increased in the presence of decreased supply.