Abstract: Reactive oxygen species are exacerbating factors in failing hearts. We examined whether spironolactone, a mineralocorticoid receptor antagonist, provides additional effects to olmesartan, an angiotensin II receptor blocker, on oxidative stress in postinfarct failing hearts. Congestive heart failure due to myocardial infarction (MI) was induced by the coronary artery ligation in rats. Three weeks later, the rats were divided into 4 groups: an untreated MI group, spironolactone (100 mg·kg−1·d−1)-treated MI group, olmesartan (10 mg·kg−1·d−1)-treated MI group, and combination-treated (spironolactone and olmesartan) MI group. After 7 weeks of MI, monotherapy improved left ventricular dilatation and function, and suppressed myocardial lipid peroxidation, in association with an attenuation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase–dependent and mitochondrial superoxide production. Moreover, combination therapy caused a synergistic improvement in these indices. In experiments using cultured myocytes, aldosterone (100 nmole/L) and angiotensin II (100 nmole/L) enhanced both sources of superoxide production, although these humoral factors affected NADPH oxidase subunits (p47phox and gp91phox) differently. In conclusion, aldosterone and angiotensin II increase NADPH oxidase–dependent and mitochondrial superoxide production in myocytes, and the combination of an angiotensin II receptor blocker and mineralocorticoid receptor antagonist has a synergistic attenuation of cardiac oxidative stress, leading to an improvement in cardiac function in postinfarct failing hearts.