Myeloperoxidase (MPO) is an important component of the oxidative antibacterial defense system of granulocytes. Mammalian MPO gene expression has been most extensively studied in human and murine cells. Transcription of the human MPO gene appears to begin at a single initiation site and we have recently described the isolation and characterization of the corresponding human MPO promoter. On the other hand, MPO transcripts in murine myeloid cells show several distinct 5′-termini, suggesting the existence of multiple murine MPO promoters. However, significant levels of endogenous murine MPO promoter activity have not been demonstrated heretofore, although several murine MPO enhancers have been described. We now report the identification and preliminary functional characterization of four distinct murine MPO promoters. Sequence comparison of the human and murine MPO promoter regions reveals homologues of three out of four of these murine promoters within the human MPO gene. However, only one of these sites appears to be functionally active in human myeloid cells, possibly because of the interposition of Alu sequences between the putative promoter sites in the human gene.