It is still unclear whether proton pump inhibitors (PPIs) could cause fundic gland polyps (FGPs) in patients without Helicobacter pylori infection. The frequency of FGPs in patients during PPI therapy has not been compared, however with a control group of patients who did not have H. pylori infection and were not undergoing PPI treatment. In a retrospective 12-month study, the frequency of FGPs in 2,251 patients without H. pylori infection receiving PPI therapy (duration of treatment at least 4 weeks) was compared with a control group of 28,096 patients who did not have H. pylori infection and were not receiving PPI therapy. FGPs were identified with an identical frequency in both groups (5.0% in the control and 5.2% in the PPI group). No significant differences were present between the groups with respect to the presence of gastritis or age or sex. Our study shows that a causal pathogenetic relationship between PPI therapy and FGPs is unlikely.