Goal: The goal of this study was to determine if there is an association between the insulin–insulin-like growth factor axis, the metabolic syndrome (MetS), type 2 diabetes mellitus and risk of Barrett’s esophagus (BE), and if these associations are modified by sex.Background: BE is more common in males. Gastroesophageal reflux disease, the major risk factor for BE occurs at similar frequencies in both sexes, suggesting that sex-related factors such as the metabolic effects of abdominal obesity may be important in the causation of BE.Materials and Methods: A structured interview, anthropometric measures, and fasting blood were collected within a population-based case-control study. We recruited 227 BE cases (70% male) and 241 population controls, frequency matched by age and sex. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for association with BE using multivariable logistic regression models.Results: Hyperinsulinemia (highest vs. lowest tertile, OR=1.9; 95% CI: 1.2-3.1), Homeostatic Model Assessment of Insulin Resistance (OR=1.9; 95% CI: 1.2-3.1) and the MetS (OR=1.8; 95% CI: 1.2-2.6) were independently associated with an increased risk of BE. With each additional MetS criterion, there was a 20% increased risk of BE (OR=1.2; 95% CI: 1.0-1.4). When stratified by sex, these associations were found in males but not females. We found no association with serum measures of insulin-like growth factors or interleukin-6 and risk of BE.Conclusion: Hyperinsulinemia, insulin resistance, and the MetS are associated with the risk of BE in males but not females, suggesting these factors may contribute to the higher prevalence of BE in males.