OBJECTIVES: Gallstones and hiatal hernia reportedly have been linked to similar dietary factors prevalent in western countries, and patients with cholelithiasis or previous cholecystectomy have been reported to have more duodenogastric reflux than healthy controls. Nonetheless, the contribution of duodenogastric reflux to the development of gastroesophageal reflux disease (GERD) remains controversial. The present study was aimed to assess the association between gallstone disease and GERD. METHODS: Outpatients from general medical clinics who underwent upper GI endoscopy and abdominal ultrasonography were recruited into a case-control study. A case population of 790 patients with various grades of GERD was compared to a control population of 407 patients without GERD. In a multivariate logistic regression, the presence of GERD served as the outcome variable, whereas the presence of gallstones, hiatal hernia, social habits, and demographic characteristics served as predictor variables. RESULTS: No associations were found between the presence of cholelithiasis or previous cholecystectomy and GERD or between the presence of cholelithiasis or previous cholecystectomy and hiatal hernia. The severity of GERD also remained unaffected by the presence of gallstones. The occurrence of GERD was influenced only by hiatal hernia (odds ratio [OR]=3.15, 95% CI=2.44-4.08), alcohol consumption (OR=1.47, CI=1.08-1.99), and not by cholelithiasis (OR=1.02, CI=0.68-1.51), or cholecystectomy (OR=0.90, CI=0.64-1.28). The frequency of GERD among hiatus hernia patients with gallstones (437/592=74%) was similar to the frequency of GERD among hiatus hernia patients without gallstones (168/220=76%, p=0.516). CONCLUSIONS: Neither cholelithiasis nor cholecystectomy poses a risk for the occurrence of GERD or hiatal hernia. Gallstone disease does not seem to influence the integrity of the esophageal mucosa through GERD.