Myeloperoxidase (MPO) catalyzes a reaction between chloride and hydrogen peroxide to generate hypochlorous acid and other reactive compounds that have been linked to DNA damage. The MPO gene is expressed at high levels in normal myeloid precursors and in acute myeloid leukemias (AMLs) which are clonal derivatives of myeloid precursors that have lost the ability to differentiate into mature blood cells. Two MPO alleles differ at -463 G/A within a cluster of nuclear receptor binding sites in an Alu element. The -463 G creates a stronger SP1 binding site and retinoic acid (RA) response element (RARE) in the allele termed Sp. In this study, we investigate potential links between MPO genotype, MPO expression level, and myeloid leukemia. The SpSp MPO genotype is shown to correlate with increased MPO mRNA levels in primary myeloid leukemia cells. This higher-expressing SpSp genotype is further shown to be overrepresented in acute promyelocytic leukemia-M3 (APL-M3) and AML-M4, suggesting that higher levels of MPO are associated with an increased risk for this subset of leukemias.