Abstract Numerous structural genetic abnormalities observed in acute myeloid leukemia (AML) illustrate the heterogeneity of this disease, which likely has contributed to difficulty in identifying susceptibility alleles for AML. We previously reported that carriers of the glutamine-encoding allele at codon 751 of the xeroderma pigmentosum group D (XPD) DNA repair gene were significantly more likely to have a karyotype associated with a less favorable prognosis, and hypothesized that this observation was driven by an association between the codon 751 variant and risk of developing AML with specific structural abnormalities. Using a case series of 927 patients with AML, we show here that the XPD codon 751 glutamine-encoding variant significantly associates with risk of developing AML with a chromosome 5q deletion (odds ratio [OR] 2.09; 95% confidence interval [CI] 1.14-3.81; n = 69; P = .02) or a chromosome 7q deletion (OR 2.27; 95% CI 1.09-4.71; n = 47; P = .03), but not with any other commonly recurring cytogenetic lesion.