BACKGROUND & AIMS: Cigarette smoking has been implicated in the etiology of esophageal adenocarcinoma, but it is not clear if smoking is a risk factor for Barrett’s esophagus (BE). We investigated whether tobacco smoking and other factors increase risk for BE. METHODS: We analyzed data from 5 case-control studies included in the international Barrett’s and Esophageal Adenocarcinoma Consortium. We compared data from subjects with BE (n=1059) with those from subjects with gastroesophageal reflux disease (GERD controls, n=1332) and population-based controls (n=1143), using multivariable logistic regression models to test associations with cigarette smoking. We also tested whether cigarette smoking has synergistic effects with other exposures, which might further increase risk for BE. RESULTS: Subjects with BE were significantly more likely to have ever-smoked cigarettes than the population-based controls (odds ratio [OR]=1.67; 95% confidence interval [CI], 1.04-2.67) or GERD controls (OR=1.61; 95% CI, 1.33-1.96). Increasing pack-years of smoking increased the risk for BE. There was evidence for a synergy between ever-smoking and heartburn or regurgitation; the attributable proportion of disease among individuals who ever smoked and had heartburn or regurgitation was estimated to be 0.39 (0.25-0.52). CONCLUSIONS: Cigarette smoking is a risk factor for BE. The association strengthened with increased exposure to smoking until ~ 20 pack-years, when it began to plateau. Smoking has synergistic effects with heartburn or regurgitation, indicating that there are various pathways by which tobacco smoking might contribute to the development of BE.