Recent evidence links obesity with the rising incidence of oesophageal adenocarcinoma. In Ireland between 1995 and 2004 the incidence of oesophageal adenocarcinoma increased by 38%, and this coincided with a 67% increase in the prevalence of obesity. In this study, a prospective case-control study was undertaken in 760 patients presenting to a tertiary centre between 1994 and 2004 diagnosed with cancer of the oesophagus, gastric cardia or stomach. Data were compared with 893 healthy controls. Multivariate logistic regression models were used to calculate the odds ratio (OR) of developing either cancer type according to quartiles of body mass index (BMI). Based on pre-illness BMI, 82% of patients who developed adenocarcinoma of the oesophagus were either overweight or obese compared with 59% of the healthy control population (P<0.001). A dose-dependent relationship existed between BMI and oesophageal adenocarcinoma in males. The adjusted odds ratio was 4.3 (95% CI: 2.3-7.9) among males in the highest BMI quartile compared with males in the lowest quartile (P<0.001 for trend). Using common cut-off points for BMI, the OR of adenocarcinoma of the lower oesophagus was 11.3 times higher (95% CI: 3.5-36.4) for individuals with a BMI >30 kg/m2 versus individuals with a BMI <22 kg/m2 (P<0.001 for trend). For adenocarcinoma of the gastric cardia, males in the top quartile of BMI had an OR of 3.5 (95% CI: 1.3-9.4) compared with the lowest quartile (P=0.03 for trend). A significant (P<0.001) inverse relationship between BMI and oesophageal SCC was observed. The odds ratio for adenocarcinoma of the oesophagus, the oesophago-gastric junction and gastric cardia rose significantly with increasing BMI. For tumours of the lower oesophagus, obesity increased the risk 10.9-fold. The increased risk is significant in males only.