Previous meta-analyses suggest that treatment with erythropoiesis-stimulating agents (ESAs) in chronic kidney disease (CKD) increases the risk for death. Additional randomized trials have been recently completed. To summarize the effects of ESA treatment on clinical outcomes in patients with anemia and CKD. MEDLINE (January 1966 to November 2009), EMBASE (January 1980 to November 2009), and the Cochrane database (to March 2010) were searched without language restriction. Two authors independently screened reports to identify randomized trials evaluating ESA treatment in people with CKD. Hemoglobin target trials or trials of ESA versus no treatment or placebo were included. Two authors independently extracted data on patient characteristics, study risks for bias, and the effects of ESA therapy. 27 trials (10 452 patients) were identified. A higher hemoglobin target was associated with increased risks for stroke (relative risk [RR], 1.51 [95% CI, 1.03 to 2.21]), hypertension (RR, 1.67 [CI, 1.31 to 2.12]), and vascular access thrombosis (RR, 1.33 [CI, 1.16 to 1.53]) compared with a lower hemoglobin target. No statistically significant differences in the risks for mortality (RR, 1.09 [CI, 0.99 to 1.20]), serious cardiovascular events (RR, 1.15 [CI, 0.98 to 1.33]), or end-stage kidney disease (RR, 1.08 [CI, 0.97 to 1.20]) were observed, although point estimates favored a lower hemoglobin target. Treatment effects were consistent across subgroups, including all stages of CKD. The evidence for effects on quality of life was limited by selective reporting. Trials also reported insufficient information to allow analysis of the independent effects of ESA dose on clinical outcomes. Targeting higher hemoglobin levels in CKD increases risks for stroke, hypertension, and vascular access thrombosis and probably increases risks for death, serious cardiovascular events, and end-stage renal disease. The mechanisms for harm remain unclear, and meta-analysis of individual-patient data and trials on fixed ESA doses are recommended to elucidate these mechanisms. None.