Abstract Background: Prevalence of Helicobacter pylori (H. pylori) infection, the main risk factor for gastric cancer, has been decreasing in the United States; however, there remains a substantial racial disparity. Moreover, the time-trends for prevalence of CagA-positive H. pylori infection, the most virulent form, are unknown in the U.S. population. We sought to assess prevalence of CagA-positive H. pylori infection over time by race in the United States. Methods: We utilized multiplex serology to quantify antibody responses to H. pylori antigens in 4,476 participants across five cohorts that sampled adults from 1985 to 2009. Using log-binomial regression models, we calculated prevalence ratios and 95% confidence intervals for the association between H. pylori–CagA sero-prevalence and birth year by race. Results: African Americans were three times more likely to be H. pylori–CagA sero-positive than Whites. After adjustment, H. pylori–CagA sero-prevalence was lower with increasing birth year among Whites (Ptrend = 0.001), but remained stable for African Americans. When stratified by sex and education separately, the decline in H. pylori–CagA sero-positivity among Whites remained only for females (Ptrend < 0.001) and was independent of educational attainment. Among African Americans, there was no difference by sex; furthermore, sero-prevalence increased with increasing birth year among those with a high school education or less (P = 0.006). Conclusions: Among individuals in the United States born from the 1920s to 1960s, H. pylori–CagA sero-prevalence has declined among Whites, but not among African Americans. Impact: Our findings suggest a widening racial disparity in the prevalence of the most virulent form of H. pylori, the main cause of gastric cancer.