Background & Aims: Eosinophilic esophagitis (EoE) is of increasing prevalence and believed to result from allergic processes. Helicobacter pylori has been inversely associated with allergic diseases, but there is no known relationship between H pylori, EoE, and esophageal eosinophilia. We investigated the association between esophageal eosinophilia and H pylori infection. Methods: We performed a cross-sectional study of data, collected from a US pathology database, on 165,017 patients in the United States who underwent esophageal and gastric biopsies from 2008 through 2010. Patients with and without H pylori on gastric biopsy were compared, and odds of esophageal eosinophilia were determined. Results: From the data analyzed, 56,301 (34.1%) had normal esophageal biopsy specimens, 5767 (3.5%) had esophageal eosinophilia, and 11,170 (6.8%) had H pylori infection. Esophageal eosinophilia was inversely associated with H pylori (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.69-0.87). Compared with patients with normal esophageal biopsy specimens, odds of H pylori were reduced among patients with ≥15 eosinophils per high-power field (eos/hpf) (OR, 0.79; 95% CI, 0.70-0.88), ≥45 eos/hpf (OR, 0.75; 95% CI, 0.61-0.93), ≥75 eos/hpf (OR, 0.72; 95% CI, 0.50-1.03), and ≥90 eos/hpf (OR, 0.52; 95% CI, 0.31-0.87) (P for trend <.001). A similar dose-response trend was observed for increasing clinical suspicion for EoE and decreasing prevalence of H pylori. Additionally, severity of histologic effects of H pylori was inversely associated with esophageal eosinophilia. All trends held in multivariate analysis. Conclusions: In a large cross-sectional analysis, H pylori infection was inversely associated with esophageal eosinophilia. This relationship could have implications for the pathogenesis and epidemiology of EoE. © 2011 AGA Institute.