Deficiency of phospholamban (PLB) results in enhancement of basal murine cardiac function and an attenuated response to β-adrenergic stimulation. To determine whether the absence of PLB also reduces the reserve capacity of the murine cardiovascular system to respond to stress, we evaluated the heart rate (HR), blood pressure, and metabolic responses of PLB-deficient (PLB−/−) mice to graded treadmill exercise (GTE). PLB−/− mice were hypertensive at rest (125 ± 19 vs. 109 ± 16 mmHg, P < 0.05) but had normal tachycardic and hypotensive responses to isoproterenol. The HR response to GTE was normal; however, the hypertension in PLB−/− mice normalized at peak exercise. Their exercise capacities, as measured by duration of exercise and peak oxygen consumption (V˙o ₂), were normal. The oxygen pulse (V˙o ₂/HR) curve was also normal in PLB−/− mice, suggesting an ability to appropriately increase stroke volume and oxygen extraction during GTE, despite an inability to increase β-adrenergically stimulated cardiac contractility. Thus deficiency of PLB, although resulting in diminished β-adrenergic inotropic reserve, does not compromise cardiac performance during exercise.