Objectives.: We evaluated the endothelial and vascular smooth muscle function in patients with chronic severe anemia to determine whether increased basal nitric oxide levels contribute to the systemic vasodilation and high cardiac output seen in these patients. Background.: Patients with chronic severe anemia have a high output state due to a low systemic vascular resistance. However, the cause of the low vascular resistance is unclear. Because hemoglobin is a potent inhibitor of endothelium-derived relaxing factor, we postulated that in chronic severe anemia, low circulating hemoglobin results in reduced inhibition of endothelium-derived relaxing factor. The basal endothelium-derived relaxing factor activity therefore increases, and this contributes significantly to the low systemic vascular resistance and the hyperdynamic state seen in this condition. Methods.: Hemodynamic variables and forearm blood flow (using plethysmography) were measured in eight patients with chronic severe anemia before (hematocrit 16 ± 2% [mean ± SD]) and within 24 h of red blood cell transfusion (n = 6, hematocrit 30 ± 1%) and in six control subjects. The effect on baseline blood flow of blocking endothelium-derived relaxing factor activity with NG.monomethyl-l-arginine was investigated. In addition, the effects of both endothelium-dependent and endotheliumindependent vasodilators on forearm blood flow were tested. Results.: Baseline forearm blood flow was markedly increased in untreated patients (6.5 ± 1.2 ml/min per 100 ml) compared with that in control subjects (2.8 ± 0.7 ml/min per 100 ml, p < 0.0001. 95% confidence interval [CI] for difference -5 to -2.5). Red blood cell transfusion significantly reduced blood flow in the anemic patients to 3.5 ± 1.1 ml/min per 100 ml (p < 0.001, 95% CI for difference -4.9 to -1.9), which was not significantly different from that in control subjects; increased systemic vascular resistance (796 ± 141 to 1,230 ± 151 dynes·s·cm-5, p < 0.001); and decreased cardiac output (4.9 ± 0.6 to 3.5 ± 0.5 liters/min per m2, p < 0.001). NG-monomethyl-l-arginine (16 μmol/min), a specific inhibitor of endothelium-derived relaxing factor, reduced forearm blood flow by an equal amount (p = 0.9, 95% CI for difference -0.7 to 0.8) in control subjects (0.98 ± 0.39 ml/min) and treated patients (1.03 ± 0.8 ml/min) but caused a threefold greater decrease in flow (2.9 ± 0.9 ml/min) in untreated patients (p = 0.0003, 95% CI for difference between untreated patients and control subjects 1.1 to 2.7). These findings suggest increased basal endothelium-derived relaxing factor activity in patients with anemia. Stimulated forearm blood flows (both endothelium dependent and endothelium independent) were similar in all groups, confirming normal endothelial and smooth-muscle function. Conclusions.: These findings support the hypothesis that enhanced basal endothelium-derived relaxing factor activity makes an important contribution to the low systemic vascular resistance in chronic severe anemia.