The objective was to investigate the association of Helicobacter pylori and serum pepsinogen (PG) levels with gastric adenocarcinoma.Serum obtained from 299 patients at the time of cancer diagnosis and from 336 population-based control subjects was tested for PG I, PG II, and antibodies to H. pylori and to CagA.Subjects with low PG I levels or low PG I/II ratios were at increased risk for cardia and noncardia gastric cancer, whereas those with H. pylori or CagA seropositivity had an elevated risk for noncardia cancer only. Subjects seropositive for either H. pylori or CagA who had low PG I levels had the highest odds ratio (OR) (9.21 [95% confidence interval {CI}, 4.95-17.13]) for noncardia cancer, compared with subjects with neither factor. Elevated risks were also found among subjects with only 1 factor (OR, 5.40 [95% CI, 2.61-11.20] for low PG I level only; OR, 4.86 [95% CI, 5.90-8.13] for H. pylori or CagA seropositivity only). This pattern persisted when PG I/II ratio replaced PG I level and when CagA seropositivity alone replaced H. pylori immunoglobulin G or CagA seropositivity.The results suggest that persons with both H. pylori or CagA seropositivity and a low PG I level or PG I/II ratio are highly susceptible to development of noncardia gastric cancer.