Many clinicians believe hypercortisolism is ulcerogenic. However, data from clinical studies show that prophylaxis for peptic ulcer disease is no longer recommended in patients receiving corticosteroid treatment. This has not yet been verified in endogenous hypercortisolism by controlled clinical studies. The purpose of the current study was to evaluate the relationship between endogenous Cushing's syndrome (CS) and peptic ulcer disease and Helicobacter pylori infection. The study group contained 20 cases with CS resulting from ACTH-dependent endogenous hypercortisolism. The control groups consisted of 14 age- and gender-matched cases receiving exogenous corticosteroid therapy and 100 cases of dyspepsia with non-cushingoid features. Upper gastrointestinal endoscopy was performed on all cases. Biopsies were taken from five different points: two samples from the antrum, two samples from the corpus, and one sample from the fundus. A histological diagnosis of Helicobacter pylori infection was also obtained from evaluation of biopsy specimens. The frequency of stomach and duodenal ulcers did not vary between the groups (p = 0.5 and p = 0.7). Antral gastritis was less frequent and pangastritis was more common in cases with CS compared to the healthy controls (p = 0.001 and p < 0.001). The incidence of Candida esophagitis was more frequent in cases with CS compared to cases with corticosteroid treatment and healthy controls (p = 0.03). Histopathological findings and frequency of Helicobacter pylori based on pathology results did not vary between the three groups. It is possible that neither exogenous nor endogenous corticosteroid excess directly causes peptic ulcer or Helicobacter pylori infection. Prophylactic use of proton pump inhibitors is not compulsory for hypercortisolism of any type.