Activation of the transcription factor signal transducer and activator of transcription (STAT)5 is involved in various aspects of hematopoiesis, affecting cell proliferation, differentiation, and cell survival. Constitutive activation of STAT5 has also been associated with leukemic transformation. We overexpressed the constitutively active mutant STAT5A(1*6) in human cord blood CD34⁺ cells and evaluated the effects on the hematopoietic potential of stem cells in a variety of in vitro and in vivo systems. The observed phenotypic changes were correlated with differential gene expression patterns induced by STAT5A(1*6). Our data indicate that a persistent activation of STAT5A in human hematopoietic stem and progenitor cells results in their enhanced self-renewal and diverts differentiation to the erythroid lineage.