OBJECTIVES: Gastroesophageal reflux symptoms occur with similar frequency in males and females, yet Barrett's esophagus is less common in females. The reason for this disparity is unknown. The aim of this study was to determine the factors related to Barrett's in females. METHODS: The records of 796 patients (462 male, 334 female) evaluated from 1990 to 2000 for symptoms of reflux were retrospectively reviewed. Physiologic abnormalities based on results of endoscopic, motility, pH, and Bilitec testing were identified, and factors related to the presence of Barrett's were determined using univariate and multivariate analysis. RESULTS: Females with reflux symptoms were significantly less likely to have a positive 24-h pH test, a defective lower esophageal sphincter, or a hiatal hernia than males with reflux symptoms. Further, females with reflux on the basis of an abnormal 24-h pH test had significantly less esophageal acid exposure than males with reflux. In contrast, esophageal exposure to refluxed acid and bilirubin was similar in females (n = 50) and males (n = 136) with Barrett's. On multivariable analysis increased esophageal bilirubin exposure was the only significant factor associated with the presence of Barrett's in male and female patients with reflux disease. CONCLUSIONS: Females with reflux symptoms have less esophageal acid exposure on average than males. However, females and males with Barrett's have a similar severity of reflux, and the female gender does not protect against the development of Barrett's in the setting of advanced reflux disease. Esophageal bilirubin exposure is the major risk factor for the presence of Barrett's in patients with reflux disease.