Fibrosis plays a central role in hypertrophic cardiomyopathy (HCM), contributing to symptoms via impaired systolic and diastolic function and ventricular arrhythmias. The aim of this study was to determine if eplerenone has an antifibrotic effect in nonobstructive HCM (resting left ventricular outflow tract gradient <30 mm Hg). This was a randomized, double-blind, placebo-controlled trial of eplerenone in 61 patients with nonobstructive HCM over 12 months. The primary endpoint was native T1 time on cardiac magnetic resonance as an index of diffuse fibrosis. Secondary endpoints included changes in diastolic function. Thirty patients were randomized to 50 mg eplerenone and 31 to placebo. There was a reduction in native T1 time within the eplerenone group (1,315 ± 134 ms at baseline vs 1,259 ± 92 ms at 12 months; P = 0.041), with no significant change in the placebo group (1,234 ± 28 ms at baseline vs 1,238 ± 70 ms at 12 months; P = 0.854). This represents a 3.7% ± 9% reduction in native T1 with eplerenone compared with a 1.1% ± 9% increase with placebo (P = 0.07). There was no significant change in functional status or markers of diastolic function (such as E/e' ratio or mitral E/A ratio). In patients with nonobstructive HCM, there was a reduction in myocardial T1 time with eplerenone, consistent with a reduction in diffuse myocardial fibrosis. Larger and longer trials are needed to confirm this finding and explore whether it translates into improved exercise capacity or a reduction in mortality over time. (Anti-fibrotic role of eplerenone on diffuse myocardial fibrosis and diastolic function in patients with hypertrophic cardiomyopathy; ACTRN12613000065796).