This study systematically reviews the randomized controlled trial (RCT) data on health-related quality of life for patients treated according to “low/intermediate” (9-12 g/dL) and “high” (>12 g/dL) hemoglobin target levels. A comprehensive search to identify all RCTs of erythropoietin-stimulating agent therapy with anemia associated with chronic kidney disease was completed. Eleven eligible studies were identified, with 9 using the 36-Item Short-Form Health Survey (SF-36). The reporting of these data was generally incomplete. Data from each domain of the SF-36 were summarized. Statistically significant changes were noted in 4 of the 8 domains: physical function (weighted mean difference, 2.9; 95% confidence interval [CI], 1.3-4.5), general health (2.9; 95% CI, 1.3-4.5), social function (2.7; 95% CI, 1.3-4.2), and mental health (0.4; 95% CI, 0.1-0.8). Targeting hemoglobin levels in excess of 12 g/dL led to small and not clinically meaningful improvements in health-related quality of life. This, in addition to significant safety concerns, suggests that targeting treatment to hemoglobin levels that are in the range of 9 to 12 g/dL is preferred.