Background and purpose Barrett’s esophagus (BE) is a pathology in which the squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium.BE can progress to esophageal adenocarcinoma (EAC). Measures to prevent the progression of BE to EAC include acid suppression therapy and early detection of EAC during endoscopic review, but studies have shown that acid exposure in the esophagus accelerates the progression of BE and contributes to the development of EAC. The aim of this study was to investigate whether acid suppression therapy could reduce the risk of BE carcinogenesis. METHODS Study design: This multicenter prospective cohort study enrolled 540 patients with BE attending 3 teaching hospitals and 12 regional hospitals in the Netherlands from November 2003 to December 2004. All BE had pathological evidence of intestinal glandular metaplasia. Exclusion criteria: BE <2 cm in length; history of anti-reflux surgery; with high-grade dysplasia (HGD) or EAC. the number of cases of HGD or EAC was obtained by follow-up. Endoscopic follow-up: Patients with BE with or without atypical hyperplasia were reviewed endoscopically and biopsied at intervals of 1 or 3 years, respectively, and at each follow-up visit patients were asked to complete a questionnaire covering demographic factors, height, weight, smoking, alcohol consumption, symptoms, and medications. Histological examination: Pathological specimens were graded by our pathologist and gastrointestinal pathologist successively, and if there was disagreement between them, another gastrointestinal pathologist was graded until at least two pathologists reached a consensus conclusion. If controversy still exists, a final diagnosis will be made by a panel of pathologists who will discuss and reach a consensus. Medications taken: information on the dose and duration of medications used was collected at each follow-up visit and the information was checked against pharmacy records; if patients applied over-the-counter medications during the follow-up visit they were also required to complete the appropriate questionnaire. At the time of enrollment, the patients were divided into current patients (>1 month), previous patients (>1 month before enrollment), and patients not using H2RAs (<1 month) according to the duration of proton pump inhibitors (PPI) and H2 receptor antagonists (H2RA). Patients with no drug use (<1 month of drug use). During the follow-up, there were two main categories: patients taking PPI and patients taking H2RA. ETHICS: The study was ethically reviewed by the Ethics Committee of Erasmus University Medical Center and the remaining participating hospitals, and the relevant informed consent forms were signed. DATA ANALYSIS: A time-dependent Cox regression model was used for modeling. SPSS 19.0 software was used for statistical analysis of the data. RESULTS PATIENT CHARACTERISTICS: The study included 540 patients with a mean follow-up period of 5.2 years. Twenty-eight patients developed HGD and 12 developed EAC during the follow-up period. Role of H2RA: H2RA had no effect on the risk of cancer in patients with BE. PPI effect: Analysis of the data showed that both PPI administration at enrollment and PPI administration during follow-up reduced the risk of BE carcinogenesis with a risk ratio (HR ) and 95% confidence interval (95% CI ) of (HR , 0.41; 95% CI , 0.18 to 0.93) and (HR , 0.21; 95% CI , 0.07 to 0.66), respectively, in addition to long-term use of PPI (P < 0.001) and taking PPI >90% of the time during follow-up (HR , 0.24; 95% CI , 0.08 to 0.71) were considered protective factors against BE carcinogenesis, but not related to the type (log rank P = 0.075) and dose (HR, 1.27; 95% CI , 0.64 to 2.49) of PPI. In addition, this study found that PPI reduced the incidence of esophagitis (Friedman P ≤ 0.001) but did not change the length of BE lesions (Friedman P = 0.179). Discussion/conclusion DISCUSSION: Spechler SJ et al. showed that pathological acid reflux was still present in 20% of BE patients with PPI, and since refluxed acid can stimulate the proliferation of esophageal epithelial cells, which may induce carcinogenesis, PPI may reduce the risk of BE carcinogenesis but does not completely block the carcinogenic process of BE. Ouatu-Lascar The present study found that PPI reduced the incidence of esophagitis but did not affect the length of BE. Therefore, it was further demonstrated that PPI reduced the risk of BE carcinogenesis but did not induce the regression of BE. Some studies have found that PPI increases the risk of EAC in patients with BE, but this finding is related to the confounding factor of the indication for PPI use, and in fact the underlying etiology of treatment with PPI, rather than PPI itself, is more likely to be a risk factor for EAC. The present study compensated for the small sample size of previous related studies and also performed a time-dependent correlation analysis. However, there are some shortcomings in this study: first, the number of BE cases without PPI is small; second, the BE length in this study is >2 cm, so it is unclear whether this conclusion applies to patients with short-segment BE; third, there may still be some uncontrollable confounding factors in this study, and in addition, although esophagitis has been considered as a factor in this study, the specific role of reflux esophagitis in the development of EAC The specific role of reflux esophagitis in the development of EAC is unclear; fourth, patients may be informed of the results of endoscopic and pathological examinations during the follow-up period, which may influence their medication use and lifestyle and thus have an impact on the study results.