There is increasing evidence that serum levels of the liver enzyme gamma-glutamyltransferase (gamma-GT) are an important predictor of incidence and mortality of various diseases. Apart from alcohol consumption, body mass index and smoking have been found to be associated with serum levels, but little is known about potential interactions of these factors. The aim of this study was to assess the individual and joint impact of alcohol consumption and smoking on levels of gamma-GT, with particular attention to potential differences by sex. The study was based on data of 8465 subjects aged 50 to 74 years, obtained at baseline examination of the ESTHER study, a large population-based cohort study in Germany. Exposure-outcome relationships were assessed in women and men, adjusting for potential confounders by multiple regression. In both sexes, moderate to heavy alcohol consumption (100+ g/week) was associated with 1.7-fold increased odds of elevated gamma-GT (>50 IU/L) in reference to nonsmoking alcohol abstainers, whereas smoking by itself was unrelated to gamma-GT. However, when moderate to heavy alcohol consumption was present in combination with heavy smoking, the odds ratios (95% CI) increased to 2.9 (1.1-7.6) in women and to 3.8 (2.2-6.6) in men (test for interaction between alcohol consumption and smoking: P(females) = 0.12, P(males) = 0.0017). CONCLUSIONS Our results support the notion of a detrimental interaction between cigarette smoking and alcohol consumption as determinants of elevated serum gamma-GT, especially in men.