Objective: Ischemic complications are common in patients with sickle cell disease. Hyperhomocysteinemia is a risk factor for arteriosclerosis and venous thrombosis, and given the propensity of patients with sickle cell disease to develop ischemic complications, we hypothesized that they might have elevated plasma homocysteine concentrations. Methods: Plasma concentrations of homocysteine, vitamin B12 and folate were measured in 49 adults with sickle cell disease and 16 normotensive Black controls. All subjects with sickle cell disease had been prescribed folic acid 1 mg by mouth daily. Results: The median plasma concentration of homocysteine of subjects with sickle cell disease was approximately 1.5-fold higher than that of controls (p=0.0008). This difference persisted, even when subjects with renal insufficiency were excluded. Plasma folate levels were 1.5-fold higher in subjects with sickle cell disease than in controls (p=0.0498). There was no significant difference in plasma vitamin B12 concentrations between the two groups. There was no difference in plasma homocysteine concentrations between transfused and non-transfused sickle cell subjects. Conclusions: Patients with sickle cell disease have elevated plasma concentrations of homocysteine in spite of elevated plasma folate levels and vitamin B12 concentrations similar to those observed in controls. Based on these data, we hypothesize that the concentration of folate required to normalize plasma homocysteine levels in patients with sickle cell disease may be higher than that of normal controls and that patients with sickle cell disease have a higher nutritional requirement for folic acid than the general population. © 2000 American College of Nutrition.