Little is known about the etiology of adenocarcinoma of the distal esophagus/cardia, a cancer which has increased in incidence in the United States over the last two decades. We analyzed data on smoking, alcohol use, dietary intake, and other factors obtained from 173 hospitalized males with adenocarcinoma of the distal esophagus/cardia (cases) and 4,544 hospitalized males with diseases not related to smoking and of other organ systems than the gastrointestinal tract (controls). Cases of squamous cell carcinoma of the esophagus (n = 136) and adenocarcinoma of the distal stomach (n = 122) were included as separate case groups. All subjects were interviewed in 28 hospitals in eight cities in the US between 1981 and 1990. After adjustment for covariates, the odds ratio (OR) for adenocarcinoma of the distal esophagus/cardia for current smokers was 2.3 (95 percent confidence interval [CI] = 1.4-3.9) and that for ex-smokers was 1.9 (CI = 1.2-3.0) relative to never-smokers. The OR for drinkers of four or more ounces of whiskey-equivalents of alcohol per day (relative to those consuming less than one drink per week) was 2.3 (CI = 1.3-4.3). Intakes of total fat and vitamin A from animal sources were significant risk factors and fiber intake was associated inversely with adenocarcinoma of the distal esophagus/cardia. Although the number of female cases of adenocarcinoma of the distal esophagus/cardia was small (n = 21), significant associations were observed for smoking and alcohol.