beta-thalassemia is an inherited hemoglobinopathy caused by defective synthesis of the beta-globin chain of hemoglobin, leading to imbalanced globin chain synthesis. Excess alpha-globin precipitates in erythroid progenitor cells resulting in cell death, ineffective erythropoiesis and severe anemia. Decreased alpha-globin synthesis leads to milder symptoms, exemplified in individuals who co-inherit alpha- and beta-thalassemia. In this study, we investigated the feasibility of utilizing short-interfering RNA (siRNA) to mediate reductions in alpha-globin expression. A number of siRNA sequences targeting murine alpha-globin were tested in hemoglobinized murine erythroleukemic cells. One highly effective siRNA sequence (si-alpha 4) was identified and reduced alpha-globin by approximately 65% at both the RNA and the protein level. Electroporation of si-alpha 4 into murine thalassemic primary erythroid cultures restored alpha :beta-globin ratios to balanced wild-type levels and resulted in detectable phenotypic correction. These results indicate that siRNA-mediated reduction of alpha-globin has potential therapeutic applications in the treatment of beta-thalassemia.