Alcohol consumption and cigarette smoking may be differentially associated with oesophageal squamous cell carcinoma (OSCC), oesophageal adenocarcinoma (OAC), gastric cardia adenocarcinoma (GCA) and gastric non-cardia adenocarcinoma (GNCA). However, because this was based on retrospective studies, these hypotheses were examined in a prospective cohort. The prospective Netherlands Cohort Study consists of 120 852 participants who completed a baseline questionnaire on diet and other cancer risk factors in 1986. After 16.3 years of follow-up, 107 OSCC, 145 OAC, 164 GCA and 491 GNCA cases were available for analysis using Cox proportional hazards models and the case-cohort approach. The multivariable adjusted incidence rate ratio (RR) for OSCC was 4.61 (95% CI 2.24 to 9.50) for > or = 30 g ethanol/day compared with abstainers (p trend <0.001), while no associations with alcohol were found for OAC, GCA or GNCA. Compared with never smokers, current smokers had RRs varying from 1.60 for GCA to 2.63 for OSCC, and were statistically significant or borderline statistically significant. Frequency, duration and pack-years of smoking were independently associated with risk of all four cancers. A positive interaction was found between alcohol consumption and smoking status regarding OSCC risk. The RR for current smokers who consumed >15 g/day of ethanol was 8.05 (95% CI 3.89 to 16.60; p interaction = 0.65), when compared with never smokers who consumed <5 g/day of ethanol. This prospective study found alcohol consumption to be associated with increased risk of only OSCC. Cigarette smoking was associated with risk of all four cancers.