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Adrenocortical carcinoma (ACC) is a rare malignancy whose risk factors are unclear. We explored the association of ACC risk with exposure to selected environmental factors, with a focus on cigarette smoking. We conducted a hospital-based case-control study at The University of Texas MD Anderson Cancer Center. Cases (n = 432) patients with ACC treated at MD Anderson, and controls (n = 1,204) were healthy and genetically unrelated spouses of patients at MD Anderson who had cancers not associated with smoking. Information on the subjects' demographic features and selected risk factors was collected using a structured, validated questionnaire and medical records review. Unconditional logistic regression was used to calculate adjusted odds ratios (AORs) via the maximum-likelihood method. Cases had a younger mean (± standard deviation) age than did controls (47.0 ± 0.7 and 60.0 ± 0.3 years, respectively), and the majority of cases were female (60.6%) and non-Hispanic white (82.4%). We found a markedly increased risk of ACC among male cigarette smokers, with an AOR = 1.8 (95% confidence interval [CI] =1.2-2.9), but not among female smokers (AOR = 1.1, 95% CI = 0.7-1.6). Family history of cancer was associated with increased risk of ACC (AOR = 2.8, 95% CI 1.9-4.3) and in both men and women, whereas alcohol consumption was associated with reduced risk in men (AOR = 0.2, 95% CI = 0.1-0.3) but not women (AOR = 0.7, 95% CI = 0.5-1.1). Understanding these risk factors and their underlying mechanisms may help prevent ACC in susceptible individuals and eventually identify new therapeutic options for ACC.