We investigated the association between Helicobacter pylori (H. pylori) infection and coronary artery disease (CAD) in 2 study populations: (1) a cross-sectional study to determine risk of having CAD, and (2) a longitudinal study to determine risk of acute myocardial infarction (AMI) or death over a mean follow-up period of 3 years in patients with angiographically documented CAD. Blood samples were tested for serum immunoglobulin G antibodies to H. pylori and C-reactive protein (CRP) levels. Study 1: Of 391 patients (62% men, mean age 57 years), 41% had antibodies to H. pylori. CAD prevalence was 70% in H. pylori seropositive patients and 59% in seronegative patients (p = 0.03). Elevated CRP levels (>0.5 mg/dl) were significantly higher in patients with than without CAD (p = 0.02). By univariate analysis, CAD prevalence significantly increased stepwise depending on H. pylori seropositivity and elevated CRP levels (p = 0.008). Significance was lost after adjustment for traditional risk factors. Further analyses revealed that age was the critical confounder. Study 2: Of 929 patients (77% men, mean age 65 years), 56% had antibodies to H. pylori. By univariate analysis, the incidence of AMI or death was 22% in H. pylori seropositive patients and 18% in seronegative patients (p = 0.1). The adjusted hazard ratio of AMI or death for H. pylori seropositivity was 1.12 (95% confidence interval 0.81 to 1.54). Our data suggest that prior infection with H. pylori is not a major factor determining either risk of CAD, AMI, or death in patients with CAD.