Background: The effect of gastrointestinal system disorders on Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) has been previously demonstrated by using serological tests. However, this association has not been supported by histopathological studies so far. Objective: To investigate the relationship between RLS/WED, upper endoscopic imaging and histopathological results in patients diagnosed with RLS who underwent endoscopy because of gastrointestinal system (GIS) complaints. Methods: Case-control study, including 100 patients diagnosed with RLS who presented dyspeptic complaints and underwent upper GIS endoscopy and 106 age- and sex-matched controls. RLS diagnosis was evaluated according to the four main diagnostic criteria determined by the International RLS Study Group. All patients underwent upper GIS endoscopic intervention and at least one gastric and/or antral biopsy. Results: There was no significant difference between patients and controls in relation to endoscopically seen gastric ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD) findings and Helicobacter pylori (HP) positivity (p>0.05). Intestinal metaplasia and mucosal atrophy were more common in RLS/WED patients compared to controls (p=0.026 and p=0.017, respectively). Additionally, ferritin levels were found to be lower than the reference value. Conclusions: The detection of increased severity of intestinal metaplasia, mucosal atrophy, and gastric inflammation in RLS/WED patients with dyspeptic complaints may entail the close gastrointestinal system evaluation of these patients. However, larger randomized and controlled trials are required on this subject where patients are evaluated by upper GIS endoscopic biopsy.