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We evaluated the influence of concomitant mineralocorticoid receptor antagonists (MRAs) on the safety and neurohumoral effects of a direct renin inhibitor in the ALiskiren Observation of Heart Failure Treatment (ALOFT) study.Patients with stable New York Heart Association class II–IV heart failure (HF), plasma B-type natriuretic peptide (BNP) concentration >100 pg/mL, and treated with an angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker) and β-blocker were randomized to once-daily, double-blind treatment with aliskiren 150 mg or placebo, added to optimal HF therapy, for 12 weeks. Safety, tolerability, and effects of aliskiren on neurohumoral biomarkers were assessed in patients who received (MRA+) and did not receive (MRA−) MRA treatment at baseline. Of the 302 randomized patients, 101 were receiving MRA treatment (aliskiren, n = 52; placebo, n = 49). Mineralocorticoid receptor antagonist status did not affect the ability of aliskiren 150 mg, added to standard HF therapy, to lower BNP, N-terminal proBNP, plasma renin activity, and urinary aldosterone. For example, the end-of-study to baseline ratio of geometric mean for BNP was: MRA+ group: aliskiren 0.68 [95% confidence interval (CI) 0.47, 0.98], placebo 0.85 (0.58, 1.24); MRA− group: aliskiren 0.62 (0.45, 0.84), placebo 0.85 (0.63, 1.15), interaction P= 0.720. The incidence of pre-specified adverse events (renal dysfunction, symptomatic hypotension, and hyperkalaemia) was low, and there were no significant differences between aliskiren and placebo in either MRA subgroup.Aliskiren 150 mg added to standard HF therapy was well tolerated over 12 weeks and provided beneficial changes in neurohumoral biomarkers regardless of concomitant MRA treatment.