BACKGROUND: An inverse association between Helicobacter pylori infection and esophageal adenocarcinoma has been reported that may be attributed to reduced acidity from inducing atrophic gastritis and from producing ammonia. We examined associations between H. pylori infection, gastric atrophy, and the risk of esophageal adenocarcinoma, esophageal squamous-cell carcinoma, and gastric cardia adenocarcinoma in a large population-based case-control study in Sweden. METHODS: Self-reported data were obtained during interviews, and serum was collected from 97 patients with incident esophageal adenocarcinoma, 85 patients with incident esophageal squamous-cell carcinoma, 133 patients with incident gastric cardia adenocarcinoma, and 499 randomly selected control subjects. Serum antibodies against whole H. pylori cell-surface antigens (HP-CSAs) and cytotoxin-associated gene A (CagA) antigens were assessed by an IgG enzyme-linked immunosorbent assay and immunoblotting, respectively. Gastric atrophy was assessed by serum levels of pepsinogen I. Multivariable logistic regression with adjustment for potential confounding factors was used to evaluate associations. RESULTS: H. pylori infection, assayed by HP-CSA or CagA antibodies, was statistically significantly associated with a reduced risk for esophageal adenocarcinoma (for HP-CSA antibodies, odds ratio [OR] = 0.3, 95% confidence interval [CI] = 0.2 to 0.6; for CagA antibodies, OR = 0.5, 95% CI = 0.3 to 0.8; for both, OR = 0.2, 95% CI = 0.1 to 0.5). Gastric atrophy was not associated with the risk for esophageal adenocarcinoma (OR = 1.1, 95% CI = 0.5 to 2.5). Serum CagA antibodies and gastric atrophy were associated with an increased risk for esophageal squamous-cell carcinoma (OR = 2.1, 95% CI = 1.1 to 4.0, and OR = 4.3, 95% CI = 1.9 to 9.6, respectively). The risk of gastric cardia adenocarcinoma was not associated with H. pylori infection. However, gastric atrophy was associated with an increased risk for gastric cardia adenocarcinoma (OR = 4.5, 95% CI = 2.5 to 7.8). CONCLUSIONS: Infection with H. pylori may reduce the risk of esophageal adenocarcinoma, but it is unlikely to do so by atrophy-reduced acidity. Gastric atrophy and infection with CagA-positive strains of H. pylori may increase the risk for esophageal squamous-cell carcinoma.