BACKGROUND: Although renin-angiotensin system (RAS) inhibitors have little demonstrable effect on mortality in patients with heart failure and preserved ejection fraction (HF-PEF), some trials have suggested a benefit with regard to reduction in HF hospitalization. METHODS AND RESULTS: Here, we systematically review and evaluate prospective clinical studies of RAS inhibitors enrolling patients with HF-PEF, including the 3 major trials of RAS inhibition (Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction [CHARM-Preserved], Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction [I-PRESERVE], and Perindopril in Elderly People with Chronic Heart Failure [PEP-CHF]). We also conducted a pooled analysis of 8021 patients in the 3 major randomized trials of RAS inhibition in HF-PEF (CHARM-Preserved, I-PRESERVE, and PEP-CHF) in fixed-effect models, finding no clear benefit with regard to all-cause mortality (odds ratio [OR] 1.03, 95% confidence interval [CI], 0.92-1.15; P=.62), or HF hospitalization (OR 0.90, 95% CI 0.80-1.02; P=.09). CONCLUSIONS: Although RAS inhibition may be valuable in the management of comorbidities related to HF-PEF, RAS inhibition in HF-PEF is not associated with consistent reduction in HF hospitalization or mortality in this emerging cohort.