Nitric oxide participates in the compensatory response to chronic vascular injury in patients with sickle cell disease. The authors have found reductions of basal and stimulated nitric oxide production and responses to exogenous nitric oxide in male patients with sickle cell disease. Gender differences in nitric oxide bioavailability are probably caused in part by the protective effects of ovarian estrogen on nitric oxide synthase expression and activity in women. Further, in men, and likely all patients during vaso-occlusive crisis and the acute chest syndrome, nitric oxide is destroyed by increased circulating plasma hemoglobin and superoxide. The combined effects of inhaled nitric oxide gas of improving pulmonary ventilation to perfusion matching and hemodynamics, reducing alveolar and systemic inflammation, and inhibiting circulating plasma hemoglobin (and thus restoring peripheral nitric oxide bioavailability) may modulate the course of the disease, including the frequency and severity of vaso-occlusive crises and acute chest syndrome episodes. Possible effects of chronic nitric oxide-based therapies on erythrocyte density, pulmonary artery pressures, and fetal hemoglobin induction deserve study.