Abstract-Allopurinol, an inhibitor of xanthine oxidase, increases myofilament calcium responsiveness and blunts calcium cycling in isolated cardiac muscle. We sought to extend these observations to conscious dogs with and without pacing-induced heart failure and tested the prediction that allopurinol would have a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. In control dogs (nϭ10), allopurinol (200 mg IV) caused a small positive inotropic effect; (dP/dt) max increased from 3103Ϯ162 to 3373Ϯ225 mm Hg/s (ϩ8.3Ϯ3.2%; Pϭ0.01), but preload-recruitable stroke work and ventricular elastance did not change. In heart failure (nϭ5), this effect was larger; (dP/dt) max rose from 1602Ϯ190 to 1988Ϯ251 mm Hg/s (ϩ24.4Ϯ8.7%; Pϭ0.03), preload-recruitable stroke work increased from 55.8Ϯ9.1 to 84.9Ϯ12.2 mm Hg (ϩ28.1Ϯ5.3%; Pϭ0.02), and ventricular elastance rose from 6.0Ϯ1.6 to 10.5Ϯ2.2 mm Hg/mm (Pϭ0.03). Allopurinol did not affect myocardial lusitropic properties either in control or heart failure dogs. In heart failure dogs, but not controls, allopurinol decreased myocardial oxygen consumption (-49Ϯ4.6%; Pϭ0.002) and substantially increased mechanical efficiency (stroke work/myocardial oxygen consumption; ϩ122Ϯ42%; Pϭ0.04). Moreover, xanthine oxidase activity was Ϸ4-fold increased in failing versus control dog hearts (387Ϯ125 versus 78Ϯ72 pmol/min ⅐ mg -1 ; Pϭ0.04) but was not detectable in plasma. These data indicate that allopurinol possesses unique inotropic properties, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of congestive heart failure. (Circ Res. 1999;85:437-445.)