Despite the high mortality rate, there is no therapy to improve survival in heart failure with preserved ejection fraction (HFpEF). Large randomized controlled trials (RCTs) did not show clear mortality benefit of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) in HFpEF. However, because of the strict enrollment criteria, the patients who participated in these trials might represent a selected group of patients that is poorly representative of patients treated in routine clinical practice. In contrast, clinical characteristics of real-world patients are similar to those of patients enrolled in observational cohort studies (OCSs). Although many OCSs have examined the prognostic effect of RAS inhibitors in HFpEF, the results are inconsistent due to limited power with small sample sizes and/or inadequate adjustment for known prognostic factors. We aimed to conduct a meta-analysis of OCSs with and those without propensity score (PS) analysis and RCTs on the effect of RAS inhibitors on mortality in HFpEF patients. The search of electronic databases identified 4 OCSs with PS analysis (10,164 patients), 8 OCSs without PS analysis (16,393 patients), and 3 RCTs (8001 patients). Use of RAS inhibitors was associated with reduced mortality in the pooled analysis of OCSs with PS analysis (RR [95% CI] = 0.90 [0.81–1.00]) and in that of OCSs without PS analysis (0.81 [0.68–0.96]) but not in that of RCTs (0.99 [0.87–1.12]). In conclusion, the present meta-analysis suggests the potential mortality benefit of RAS inhibitors in HFpEF, emphasizing the importance of conducting new well-designed RCTs.