ABSTRACT The Helicobacter pylori vacA gene encodes a secreted protein (VacA) that alters the function of gastric epithelial cells and T lymphocytes. H. pylori strains containing particular vacA alleles are associated with differential risk of disease. Because the VacA midregion may exist as one of two major types, m1 or m2, serologic responses may potentially be used to differentiate between patients colonized with vacA m1 - or vacA m2 -positive H. pylori strains. In this study, we examined the utility of specific antigens from the m regions of VacA as allele-specific diagnostic antigens. We report that serological responses to P44M1, an H. pylori m1-specific antigen, are observed predominantly in patients colonized with m1 -positive strains, whereas responses to VacA m2 antigens, P48M2 and P55M2, are observed in patients colonized with either m1 - or m2 -positive strains. In an Asian-American population, serologic responses to VacA m region-specific antigens were not able to predict the risk of development of gastric cancer.