Enhanced erythrocyte destruction in sickle cell anemia results in chronic hyperbilirubinemia. Only a subset of patients develop cholelithiasis.UGT1A1promoter polymorphism is associated both with unconjugated bilirubin level and elevated risk for cholelithiasis in such subset. Here, we investigated the role of a-thalassemia, yet another genetic factor that modulates hemolysis, in conferring protection from cholelithiasis. We show that, although a-thalassemia is associated with modest reduction in hemolysis and unconjugated bilirubin level, UGT1A1 polymorphism outweighs its effect on cholethiogenesis in sickle cell anemia patients. Am. J. Hematol. 81:377-379, 2006. © 2006 Wiley-Liss, Inc.