Background Anemia in heart failure is both common and associated with worse symptoms and increased mortality. Several small randomized controlled trials (RCTs) have assessed erythropoiesis-stimulating agents (ESAs), but definitive evaluation and clinical guidance are required. We sought to systematically review the effects of ESAs in chronic heart failure. Methods An extensive search strategy identified 11 RCTs with 794 participants comparing any ESA with control over 2 to 12 months of follow-up. Published and additionally requested data were incorporated into a Cochrane systematic review (CD007613). Results Nine studies were placebo controlled, and 5, double blinded. Erythropoiesis-stimulating agent treatment significantly improved exercise duration by 96.8 seconds (95 CI 5.2-188.4, P = .04) and 6-minute walk distance by 69.3 m (95 CI 17.0-121.7, P = .009) compared with control. Benefit was also noted for peak oxygen consumption (+2.29 mL/kg per minute, P = .007), New York Heart Association class (a??0.73, P <.001), ejection fraction (+5.8 , P <.001), B-type natriuretic peptide (a??226.99 pg/mL, P <.001), and quality-of-life indicators with a mean increase in hemoglobin level of 2 g/dL. There was a significantly lower rate of heart failurea??related hospitalizations with ESA therapy (odds ratio 0.56, 95 CI 0.37-0.84, P = .005). No associated increase in adverse events or mortality (odds ratio 0.58, 95 CI 0.34-0.99, P = .047) was observed, although the number of events was limited. Conclusion Meta-analysis of small RCTs suggests that ESA treatment can improve exercise tolerance, reduce symptoms, and have benefits on clinical outcomes in anemic patients with heart failure. Confirmation requires larger, well-designed studies with careful attention to dose, attained hemoglobin level, and long-term outcomes.