We have constructed a “minilocus” that contains the 5’and 3’flanking regions of the human P-globin locus and the B-globin gene. These regions are characterized by erythroid-specific DNAase I-superhypersensitive sites and are normally located approximately 50 kb 5’and 20 kb 3’of the P-globin gene. This minilocus is expressed tissue-specifically in transgenic mice at a level directly related to its copy number yet independent of its position of integration in the genome. Moreover, the expression per gene copy is the same in each mouse and as high as that of the endogenous mouse P-globin gene. These results indicate that the DNA regions flanking the human P-globin locus contain dominant regulatory sequences that specify position-independent expression and normally activate the complete human multigene P-globin locus.