Reversal of cardiac fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness versus the mineralocorticoid receptor antagonist potassium canrenoate to reverse established cardiac fibrosis. Male lean spontaneously hypertensive heart failure (SHHF) rats (40 weeks) were treated for 8 weeks by subcutaneous infusions of low (0.24 mg/kg.day) or high (1.2 mg/kg.day) doses of R- or S-fadrozole or by potassium canrenoate via drinking water (7.5 mg/kg.day). At the high dose, plasma aldosterone levels were decreased similarly by R- and S-fadrozole, while urinary aldosterone excretion rate was only reduced by S-fadrozole. In contrast, whereas at the high dose R-fadrozole effectively reversed pre-existent left ventricular interstitial fibrosis by 50% (versus 42% for canrenoate), S-fadrozole was devoid of an antifibrotic effect. The low doses of the fadrozole enantiomers did not change cardiac fibrosis or plasma aldosterone but similarly reduced urinary aldosterone excretion rate. In conclusion, R-fadrozole may possess considerable therapeutic merit because of its potent antifibrotic actions in the heart. However, the observed discordance between the aldosterone-lowering and antifibrotic effects of the fadrozole enantiomers raises some doubt about the mechanism by which R-fadrozole diminishes cardiac collagen and about the generality of the concept of lowering aldosterone levels to treat the diseased heart.