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The estimated association betweenHelicobacter pyloriand Barrett's esophagus (BE) has been heterogenous across previous studies. In this study, we aimed to examine the association betweenH. pyloriand BE and to identify factors that may explain or modify this association.We conducted a case–control study in which we used screening colonoscopy controls recruited from primary care clinics as our primary control group in order to minimize selection bias. All participants underwent an esophagogastroduodenoscopy with gastric mapping biopsies. We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the association betweenH. pyloriand BE while controlling for confounders.We identified 218 cases and 439 controls. The overall OR for the association betweenH. pyloriand BE after controlling for age and white race was 0.55 (95% CI: 0.35–0.84). We observed an even stronger inverse association (OR: 0.28; 95% CI: 0.15, 0.50) among participants with corpus atrophy or antisecretory drug use ≥1 time per week (factors thought to lower gastric acidity), and no inverse association in patients without these factors (OR: 1.32; 95% CI: 0.66, 2.63).The association betweenH. pyloriand a decreased risk for BE appears to occur in patients with factors that would likely lower gastric acidity (corpus atrophy or taking antisecretory drugs at least once a week).