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Background & Aims Previous studies reported an association of the bacteria Helicobacter pylori , the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. Methods We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. Results Overall, 40% of controls and 41% of cases were H pylori –seropositive (odds ratio [OR], 1.09; 95% CI, 0.99–1.20). H pylori VacA–specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01–1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08–1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P =.008) and specifically among African Americans (P =.007). Conclusions In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations. Graphical abstract [ABSTRACT FROM AUTHOR]