Sickle cell disease patients have a high risk of developing leg ulcers. In the CSSCD database we found 378 patients with a confirmed history of leg ulcers and chose 920 patients without ulcers to serve as controls. α Thalassemia reduces hemolysis in sickle cell anemia which is consistent with our finding using an age-adjusted comparison, that sickle cell anemia-α thalassemia was more frequent among controls than cases (OR: 0.7, 95% CI: 0.5–0.9). This suggests that sickle cell anemia-α thalassemia patients are significantly less likely to have leg ulcers. Also, leg ulcer patients had lower hemoglobin levels, higher LDH, bilirubin, AST, reticulocyte and white blood cell count than controls. These differences were highly statistically significant (p < 0.001, except for AST, whose p was <0.005) and support the impression that cases have a higher rate of hemolysis than controls. Fetal hemoglobin was higher in controls compared with cases (p=0.002). The haplotype of the β-like globin gene cluster, creatinine and ALT were not associated with leg ulcers. Leg ulcers were associated with other clinical manifestations of sickle cell disease like ischemic stroke (OR:1.4, 95% CI: 0.9–2.0) and acute chest syndrome (OR:1.5, 95% CI:1.1–1.9). When analysis of laboratory data was restricted to the 759 patients (243 cases vs. 516 controls) that were also genotyped for SNPs in candidate genes, the results were similar. We studied 132 SNPs in 47 candidate genes for their association with leg ulcers. SNPs were studied by mass spectrometry in a screening phase and by using haplotype tagging (ht) SNPs and the ABI SNPlex for follow-up. Candidate genes included: mediators of inflammation; oxidant injury; NO biology; vasoregulation; cell-cell interaction; blood coagulation; hemostasis; growth factors; cytokines and receptors. The candidate genes having multiple SNPs associated with leg ulcers were KL (rs685417 and rs516306; p values <0.02), TEK (rs603085 and rs671084; p values <0.025), SMAD1 (rs1899784, rs10519733 and rs2068991; p values <0.05), and SARA1 (rs2271690 and rs870801; p values <0.04). KL directly or indirectly promotes endothelial NO production. The TEK receptor tyrosine kinase (TIE2) is expressed almost exclusively in endothelial cells, is involved in angiogenesis and is the ligand for angiopoietin-1 (ANG1). SMAD1 and SARA1 are members of the TGF-β/BMP pathway. The TGF-β receptor signals through the SMAD family of transcriptional regulators that are anchored to the cell membrane by factors like SARA (SMAD Anchor for Receptor Activation). This pathway modulates immunosuppression, cell migration, wound healing and angiogenesis, among its other functions. Hemolysis is likely to be an antecedent of certain vascular complications of sickle cell disease, like pulmonary hypertension This, and the current studies, suggest that there is a hemolysis-driven phenotype in sickle cell disease that now includes leg ulcers. While candidate genes that might modulate the rate of hemolysis have not yet been studied, we find that SNPs in genes that may be pathogenetically important in sickle vasculopathy are associated with the disease subphenotype of leg ulcer. Linking gene polymorphisms with disease subphenotypes, may eventually provide useful means of foretelling the likelihood of complications and allow better individualized treatment.