Heart failure with preserved ejection fraction (HF-PEF) is a well-recognized complication of long-standing hypertension. However, beyond the control of the traditional cardiovascular risk factors, there are few other recommendations for its management. To examine the potential benefit of renin-angiotensin system (RAS) inhibition in HF-PEF, we performed a systematic review of the published medical literature. MEDLINE, EMBASE, and COCHRANE databases were searched from 1966 to 2011 for longitudinal studies examining HF-PEF patients receiving treatment with RAS inhibitors, either ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARB) in addition to their standard treatment compared to those receiving standard treatment alone. We examined the all-cause mortality, cardiovascular mortality, and hospitalizations for heart failure. A total of 12 studies with 11,259 participants were included in the analysis. Among the randomized clinical trials, with the use of RAS inhibitors over standard treatment, there was no improvement in all-cause mortality (RR: 0.99; 95% CI: 0.88-1.12; p = 0.88), while there was a trend toward lowered rates of hospitalization (RR: 0.93; 95% CI: 0.86-1.01; p = 0.08). There were no major differences in the outcomes between the ACE-I or ARB. However, among the observational studies with the use of RAS inhibitors, there was a significant benefit in all-cause mortality (RR: 0.76; 95% CI: 0.62-0.93; p = 0.009), with no significant impact on the hospitalization rates. RAS inhibition in HF-PEF was not associated with significant reduction in all-cause or cardiovascular mortality, but randomized control trials appear to demonstrate a trend toward reduction in the risk for subsequent hospitalization. Further prospective randomized trials are warranted to confirm the effects of RAS inhibition on mortality and hospitalization.