We and others have published biochemical and physiological evidence supporting a model in which intravascular hemolysis and oxidant stress in patients with sickle cell disease (SCD) results in impaired nitric oxide (NO) bioavailability, with an associated reduction in NO-dependent blood flow. This reduced bioavailability is characterized by NO destruction and thus a resistance to both endogenous and exogenous (nitroprusside, nitroglycerin, NONOates) NO. A crucial regulator of endothelial cell homeostasis, NO regulates basal vasodilation, inhibits platelet aggregation, and tonically inhibits expression of cell adhesion molecules by endothelial cells, including vascular cell adhesion molecule (VCAM-1). Statins have been reported to both improve NO-dependent blood flow and reduce oxidant stress in patients with hypercholesterolemia and in normal subjects. We therefore investigated whether atorvastatin has similar effects in patients with SCD. Five patients have completed the study (targeted enrollment will be 15 patients); patients were selected for suspected NO-dependent vascular dysfunction as determined by higher than median plasma levels of soluble VCAM-1 or pulmonary hypertension (tricuspid regurgitant jet velocity > 2.4 meters/second). Baseline vascular reactivity to arterial infusions of sodium nitroprusside (SNP), acetylcholine (ACh), and the inhibitor of endothelial NO synthesis, L-NG-monomethyl-L-arginine (L-NMMA) at increasing doses was assessed by forearm venous occlusion plethysmography. Patients took atorvastatin 10 mg daily for two weeks, then 20 mg daily for another two weeks, and forearm studies were repeated. All patients tolerated the drug without adverse effects. Plasma total cholesterol levels decreased in all patients, (baseline 115 ± 5 mg/dL, post-treatment 93 ± 5 mg/dL (mean ± SEM), p=0.002). Serum creatine kinase increased slightly, but remained in the normal range (55 ± 9 vs. 73 ± 18 IU/L, p=0.15). All patients had markedly impaired responses at baseline to SNP, ACh and L-NMMA compared to healthy control subjects, validating our screening methodology to identify subjects with NO resistance. After four weeks of oral atorvastatin therapy, responsiveness to both SNP and ACh significantly improved in each group compared to baseline by ANOVA with repeated measures (p < 0.05). Response to L-NMMA was not significantly affected. These data provide a non-invasive strategy for identifying patients with NO-resistance (endothelial dysfunction) by screening soluble VCAM-1 levels and tricuspid regurgitant jet velocities, and further suggest that high pulmonary artery systolic pressures in this population are associated with reduced NO bioavailability. Additionally, we show that short term use of the FDA approved medication atorvastatin, is safe in this population. Our data are consistent with statin-mediated improvement in vascular responsiveness to NO that is independent of improved endothelial NO production, and support consideration of statins in clinical trials to reduce vascular occlusion in patients with SCD.