BACKGROUND Several epidemiological and clinical reports have suggested seropositivity for Helicobacter pylori may be a risk factor for coronary heart disease. However, there has been no prospective study of this association involving an ethnically diverse sample of middle-aged men and women. RESULTS Using a prospective, case-cohort design, we determined H pylori seropositivity in relation to coronary heart disease incidence over a median follow-up period of 3.3 years among middle-aged men and women. There were 217 incident coronary heart disease cases and a cohort sample of 498. We determined H pylori antibody status by measuring IgG antibody to the high-molecular-weight cell-associated proteins of H pylori using a sensitive and specific ELISA. The prevalence of H pylori seropositivity was higher in blacks than whites, in those with less than high school education, in those with lower plasma pyridoxal 5'-phosphate and higher homocyst(e)ine concentrations, in those who did not use vitamin supplements, in those with higher fibrinogen levels, and in those seropositive for cytomegalovirus and herpes simplex type I (all P<0.05). The age-, sex-, race-, and field center-adjusted hazard ratio of coronary heart disease for H pylori seropositivity was 1.03 (95% CI=0.68 to 1.57). After adjustment for other risk factors, including fibrinogen, cytomegalovirus seropositivity, and herpes simplex type I seropositivity, the hazard ratio was 0.85 (95% CI=0.43 to 1.69). H pylori seropositivity also was not associated with increased mean intima-media thickness of the carotid artery, a measure of subclinical atherosclerosis. CONCLUSIONS H pylori infection is probably not an important contributor to clinical coronary heart disease events.