Background: Chronic kidney disease (CKD) is common in systolic heart failure (SHF) and is associated with poor outcomes. It is also associated with underuse of angiotensin-converting enzyme (ACE) inhibitors, yet the effect of these drugs in these (SHF-CKD) patients has not been well studied. The objective of this analysis was to determine if ACE inhibitor use was associated with reduction in mortality and hospitalization in SHF-CKD patients. Methods and Results: Of the 6800 SHF patients (ejection fraction ≤45%) in the Digitalis Investigation Group trial, 1707 had CKD (serum creatinine 1.3-2.5 mg/dL for women and 1.5-2.5 mg/dL for men). Propensity scores for ACE inhibitor use were calculated for each of the 1707 patients and were used to match 104 of the 127 no-ACE inhibitor patients with 104 ACE inhibitor patients. We estimated the effect of ACE inhibitor use on outcomes at 2 years using multivariable-adjusted Cox regression analyses. Overall, 35% of patients died and 67% were hospitalized. Compared with 30% of ACE inhibitor patients, 39% of no-ACE inhibitor patients died (adjusted HR = 0.58; 95% CI = 0.35-0.96; P = .034). Compared with 64% of ACE inhibitor patients, 69% of no-ACE inhibitor patients had hospitalizations from all causes (adjusted HR = 0.69; 95% CI = 0.48-0.98; P = .040). Conclusion: We observed an association between use of ACE inhibitor and reductions in mortality and hospitalization in ambulatory chronic SHF patients with mild to moderate CKD. However, the results of this observational study should be interpreted with caution, and need to be replicated in larger and more recent databases, and confirmed prospectively in well-designed follow-up studies and/or randomized clinical trials. © 2006 Elsevier Inc. All rights reserved.