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BACKGROUND: Acute myeloid leukemia (AML) is comprised of several bone marrow-based cancers and is the most common type of leukemia in the United States. The etiology of AML is not well understood. A case-control study was conducted at The University of Texas M. D. Anderson Cancer Center to investigate associations between lifestyle characteristics and the risk of AML in Texas. METHODS: This study included 638 adult patients with de novo AML (cases) and a group of 636 matched controls. Interviewer-administered questionnaires were used to collect demographic and occupational data. The distribution of cases by World Health Organization (WHO) subtype was 71 patients (11%) with recurrent cytogenetic abnormalities (AML-RCA), 134 patients (21%) with multilineage dysplasia (AML-MD), and 389 patients (61%) with AML not otherwise categorized (AML-NOC). Multivariate logistic regression analyses were performed among all AML cases and among both sexes and each WHO subgroup. RESULTS: Among men, heavy smoking (≥30 pack-years; odds ratio [OR], 1.86) and occupational solvent exposure at low levels (OR, 2.87) or moderate/high levels (OR, 4.13) statistically significantly increased the risk of AML. Among women, obesity (OR, 1.62) and solvent exposure to low levels (OR, 2.73) or moderate/high levels (OR, 3.90) increased the risk of AML. Across WHO subtypes, obesity was associated with a statistically significantly increased risk of AML-RCA (OR, 3.15), whereas solvent exposure increased the risk in all subtypes at low levels (AML-RCA: OR, 4.11; AML-MD: OR, 2.54) and moderate/high levels (AML-RCA: OR, 5.13; AML-MD: OR, 3.02). A joint effect between smoking and solvent exposure was observed, and the highest risk was observed among smokers who had solvent exposure (OR, 4.51). CONCLUSIONS: The current results suggested that several factors play a role in AML predisposition with possible joint effects. Risk profiles for AML differed by sex and WHO subtype. Cancer 2012. © 2012 American Cancer Society.