To date, all major clinical trials for anemia correction using erythrocyte stimulating agents (ESAs) failed to show improved outcomes for cardiovascular disease (CVD), stroke, and vascular thrombosis. Even moderate elevations in hemoglobin (e.g., to 13 g/dL) using erythropoietin have been associated with significantly increased risk of thrombotic cardiovascular events and heart failure. This review presents a biophysical rationale for increased risk of CVD among certain patients treated with ESAs and suggests a risk management approach based on blood viscosity. Whole blood viscosity is a key determinant of the work of the heart, and elevated blood viscosity appears to be both a strong predictor of cardiovascular disease and an important pathophysiological factor in the development of atherothrombosis. Blood donation has been shown to reduce viscosity. Reflecting these findings, studies in male blood donors and in women of premenopausal age with regular menstruation have shown reduced incidence of cardiovascular events such as myocardial infarction, angina, stroke, and the requirement for procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass graft compared with non-donors and postmenopausal women, respectively. We propose that blood viscosity monitoring should be considered as part of a cardiovascular risk assessment, whenever an increased cardiovascular risk is detected and particularly in the context of anemia correction.