Adrenal cancer is a rare and heterogenous group of tumors the etiology of which is largely unknown. Tobacco use was suggested as a potential risk factor in a recent case-control study of adults dying from adrenal cancers, most of which were adrenocortical carcinomas. In a cohort study of nearly 250,000 United States veterans whose mortality was followed for up to 26 years, we evaluated the risk of adrenal cancer associated with tobacco use. Relative risks and corresponding 95% confidence intervals were calculated. A total of 27 adrenal cancer deaths were observed during the follow-up period. Relative to nonusers of any tobacco, risk was elevated 5-fold (relative risk = 5.1; confidence interval = 1.1-22.4) among current cigarette smokers, with risks further increased among those who smoked > 20 cigarettes/day (P for trend < 0.01). Nonsignificant increases in risk occurred among smokers of other forms of tobacco. This cohort study provides support for an etiological relationship between tobacco smoking and adrenal cancer, although further confirmatory studies are needed.