b-Globin locus control region (LCR) sequences have been widely used for the regulated expression of the human b-globin gene in therapeutic viral vectors. In this study, we compare the expression of the human b-globin gene from either the HS2/HS3 b-globin LCR or the HS40 regulatory element from the a-globin locus in the context of foamy virus (FV) vectors for the genetic correction of b-thalassemia. Both regulatory elements expressed comparable levels of human b-globin in a murine erythroleukemic line, whereas in murine hematopoietic stem cells the HS40.b vector proved more efficient in b-globin expression and correction of the b-thalassemia phenotype. Following transplantation in the Hbb th3/+ mouse model, the expression efficiency by the two vectors was similar, whereas the HS40.b vector achieved relatively more stable transgene expression. In addition, in an ex vivo assay using CD34+ cells from thalassemic patients, both vectors achieved significant human b-globin expression and restoration of the thalassemic phenotype as evidenced by enhanced erythropoiesis and decreased apoptosis. Our data suggest that FV vectors with the a-globin HS40 element can be used as alternative but equally efficient vehicles for human b-globin gene expression for the genetic correction of b-thalassemia.