Background & Aims: Infection with Helicobacter pylori is associated with reduced risk of esophageal adenocarcinoma (EAC), but it is not clear whether this reduction is modified by genotype, other host characteristics, or environmental factors. Furthermore, little is known about the association between H pylori and adenocarcinomas of the esophagogastric junction (EGJAC) or squamous cell carcinomas (ESCC). We sought to measure the association between H pylori infection and esophageal cancer and identify potential modifiers. Methods: In an Australian, population-based, case-control study, we compared the prevalence of H pylori seropositivity and single nucleotide polymorphisms in interleukin (IL)-1B (-31, -511) and tumor necrosis factor (TNF)-α (-308, -238) among 260 EAC, 298 EGJAC, and 208 ESCC patients and 1346 controls. To estimate relative risks, we calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression in the entire sample and within strata of phenotypic and genotypic risk factors. Results: H pylori infection was associated with significantly reduced risks of EAC (OR, 0.45; 95% CI: 0.30-0.67) and EGJAC (OR, 0.41; 95% CI: 0.27-0.60) but not ESCC (OR, 1.04; 95% CI: 0.71-1.50). For each cancer subtype, risks were of similar magnitude across strata of reflux frequency and smoking status. We found no evidence that polymorphisms in IL-1B or TNF-α modified the association between H pylori and EAC or EGJAC. Conclusions: H pylori infection is inversely associated with risks of EAC and EGJAC (but not ESCC); the reduction in risk is similar across subgroups of potential modifiers.