To ascertain the frequency and the clinico-functional correlations of intramucosal cysts in the gastric body of patients with the Zollinger-Ellison syndrome (ZES) and to clarify the relevant mechanism of development, a total of 106 consecutive ZES patients (58 M, 48 F; mean age: 53 yrs, range 19-93 yrs) were investigated with a mean of 7.2 biopsy specimens of the body mucosa per patient proved to be suitable for the study. Biopsies of endoscopically detectable polypoid lesions were not considered. Cystic changes were evaluated with respect to their severity by assessing the cyst grade (0, absent, 1; <30%, 2; 30-60%; 3 >60% of the mucosal area of the biopsy specimen of individual patients showing the most pronounced finding, respectively) and to their intragastric distribution by assessing the ratio of biopsy specimens showing cystic changes over the total number of biopsies examined in each patient. Intramucosal cysts were found in biopsies of non-polypoid gastric body mucosa in 71.7% of 106 patients with Zollinger-Ellison syndrome (ZES) and showed grade 2 and 3 severity in 22 and 8 cases, respectively. The severity of cystic changes correlated with the gastrin levels (p = 0.0005) and was more advanced in patients with active than in those with cured disease (p = 0.037). In the former group, furthermore, advanced cystic changes correlated with age (p = 0.03), male gender (p = 0.014), years of disease from onset (p < 0.02), years of omeprazole treatment (p = 0.033), basal acid output (p < 0.02), severity of ECL cell proliferative changes (p = 0.028), and absence of previous gastrinoma resection (p = 0.039) whereas they did not correlate with MEN-1 status, gastritis, maximal acid output, total duration of any antisecretory drug treatment, daily doses of omeprazole (> 20 mg vs 20 mg), years from surgery, duodenal localization of gastrinoma(s), presence of gastric carcinoid tumor(s) and of liver metastases. In groups of patients subdivided according to three levels of serum gastrin, the duration of omeprazole treatment was not related to the severity of cystic changes. It is concluded that intramucosal cysts in non polypoid gastric body mucosa of ZES patients are by far more common than the already reported fundic gland polyps, to which they likely give raise. Circulating levels of gastrin have an important independent role in their development.