PURPOSE: The authors recently reported high Helicobacter pylori sero-prevalence among African-Americans of high African ancestry. We sought to determine whether neighborhood-level socio-economic characteristics are associated with H. pylori prevalence and whether this helps explain the link between African ancestry and H. pylori. METHODS: Antibodies to H. pylori proteins were assessed in the serum of 336 African-American and 329 white Southern Community Cohort Study participants. Prevalence odds ratios (ORs) and 95 % confidence intervals (CIs) for CagA+ and CagA- H. pylori were calculated using polytomous logistic regression in relation to 10 Census block group-level measures of socio-economic status. RESULTS: After adjusting for individual-level characteristics, three neighborhood-level factors were significantly inversely related to CagA+ H. pylori: percent completed high school; median house values; and percent employed (comparing highest to lowest tertile, OR, 0.47, 95 % CI, 0.26-0.85; OR, 0.56, 95 % CI, 0.32-0.99; and OR, 0.59, 95 % CI, 0.34-1.03, respectively). However, accounting for these measures did not attenuate the association between African ancestry and CagA+ H. pylori, with African-Americans of low, medium, and high African ancestry maintaining two-, seven-, and ninefold increased odds, respectively, compared to whites. CONCLUSIONS: Neighborhood-level measures of education, employment, and house values are associated with CagA+ H. pylori sero-prevalence, but do not explain the persistent strong relationship between African ancestry level and CagA+ H. pylori. The findings suggest that neighborhood socio-economic status can help to highlight high-risk areas for prevention and screening efforts and that the link between African ancestry and H. pylori may have a biological basis.