Abstract Surface hydrophobicity of the gastric mucosa is reduced in peptic ulcer disease and Helicobacter pylori infection. This abnormality may be caused by H. pylori or may be an inherent defect. The aim of the present study was to clarify the relationship between H. pylori infection and mucosal hydrophobicity by examining the effect of eradication of the organism. H. pylori-positive patients with (n = 42) or without (n = 42) duodenal ulcer were randomized to receive ranitidine, bismuth, or bismuth plus antibiotics. Surface hydrophobicity of gastric mucosa was assessed by measurement of plateau-advancing contact angle. Measurements were performed at presentation, end of treatment, and 1 month later. Contact angle was unchanged after ranitidine (55 ° vs. 56 °) but increased with bismuth (57 °–62 °; P < 0.05) and bismuth plus antibiotics (56 °–67 °; P < 0.0001). One month after treatment ended, contact angles in patients in whom H. pylori was not eradicated were not different from those before treatment (56 ° vs. 56 °) but increased to a value similar to H. pylori-negative controls in patients in whom H. pylori was eradicated (56 °–69 °; P < 0.0001). It is concluded that reduced mucosal hydrophobicity in peptic ulcer disease is secondary to H. pylori infection and that this impaired mucosal defense provides a possible mechanism whereby H. pylori infection predisposes to acid/ peptic digestion.