We analyzed the association between history of cancer in first-degree relatives and the risk of squamous cell carcinoma of the esophagus (SCCE) using data from three case-control studies conducted in Italy and Switzerland on 805 incident, histologically confirmed SCCE, and 3,461 hospital controls. The alcohol- and tobacco-adjusted odds ratio (OR) for a family history of esophageal cancer was 3.2 [95% confidence interval (CI), 1.7-6.2], and the OR was higher when the affected relative was a brother or was diagnosed at age <55 years. Compared to subjects without family history of esophageal cancer, non-current smokers, drinking <49 drinks per week, the OR was 2.9 (95% CI, 1.1-7.5) for family history alone, 15.5 (95% CI, 11.7-20.5) for current smokers drinking > or = 49 drinks per week without family history of esophageal cancer, and 107.0 (95% CI, 13.0-880.2) for current smokers drinking > or = 49 drinks per week who also had a family history of esophageal cancer. The risk of SCCE was also increased in subjects with a family history of cancer of the oral cavity/pharynx (OR, 3.7; 95% CI, 1.5-9.0) and stomach (OR, 2.0; 95% CI, 1.1-3.6), but not of other cancers, nor for a family history of any cancer (OR, 1.0; 95% CI, 0.8-1.4). These data show that, as for many other epithelial cancers, the risk of SCCE is increased in subjects with a family history of the disease, and that--in Western countries--avoidance of alcohol and tobacco is also the best way to prevent SCCE in subjects with a family history of the disease.