AIMS: The renin-angiotensin-aldosterone system (RAAS) represents a key therapeutic target in heart failure (HF) management. However, conventional agents that block this system induce a reflex increase in plasma renin activity (PRA), which may lead to RAAS 'escape'. Direct renin inhibitors (DRIs) have been developed that decrease PRA and thus may provide a greater RAAS blockade. Aliskiren is the first orally active DRI. Plasma levels of B-type natriuretic peptide (BNP) have been observed to be reduced with aliskiren compared with placebo. The aim of the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE) study is to evaluate the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on cardiovascular death and HF hospitalization in patients with chronic systolic HF, NYHA functional class II-IV symptoms, and elevated plasma levels of BNP. Methods Patients tolerant to at least 10 mg or equivalent of enalapril will undergo an open-label run-in period where they receive enalapril then aliskiren. Approximately 7000 patients tolerating this run-in period will then be randomized 1:1:1 to aliskiren monotherapy, enalapril monotherapy, or the combination. The primary endpoints of ATMOSPHERE are (i) whether the aliskiren/enalapril combination is superior to enalapril monotherapy in delaying time to first occurrence of cardiovascular death or HF hospitalization and (ii) whether aliskiren monotherapy is superior or at least non-inferior to enalapril monotherapy on this endpoint. Perspective The ATMOSPHERE study will definitively determine the role of a DRI strategy additional to or as an alternative to conventional RAAS blockade in patients with chronic systolic HF.