Background Heart failure is the leading cause for 30-day all-cause readmission, the reduction of which is a goal of the Affordable Care Act. There is a growing interest in understanding the impact of evidence-based heart failure therapy on 30-day all-cause readmission. In the current study, we examined the impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI-ARBs) on 30-day all-cause readmission in heart failure. Methods Of the 1384 hospitalized Medicare beneficiaries with heart failure and left ventricular ejection fraction <45% discharged alive from 106 Alabama hospitals (1998-2001) without prior ACEI-ARB use and without known contraindications to ACEI-ARB use; 734 received new predischarge prescriptions for these drugs. Using propensity scores for ACEI-ARB initiation, we assembled a matched cohort of 477 pairs of patients balanced on 32 baseline characteristics (mean age 75 years, 46% women, 26% African American). Results Thirty-day all-cause readmissions occurred in 18% and 24% of matched patients receiving and not receiving ACEI-ARBs, respectively (hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.56-0.97; P = .030). ACEI-ARB use was also associated with lower risk of 30-day all-cause mortality (HR 0.56; 95% CI, 0.33-0.98; P = .041) and of the combined endpoint of 30-day all-cause readmission or 30-day all-cause mortality (HR 0.73; 95% CI, 0.56-0.94; P = .017). All associations remained significant at 1 year post discharge. Conclusions Among hospitalized patients with heart failure and reduced ejection fraction, the use of ACEI-ARBs was associated with a significantly lower risk of 30-day all-cause readmission and 30-day all-cause mortality; both beneficial associations persisted during long-term follow-up.