BACKGROUND: Helicobacter pylori infection is an established risk factor for gastric adenocarcinoma. Potential confounding by socioeconomic factors has not been adequately assessed, and the magnitude of the relative risk in relation to gastric subsites, morphologic subtypes, sex, age, and follow-up time need further study. METHODS: We conducted a serologic case-control study nested within the Norwegian JANUS cohort. Between 1972 and 1986 serum was collected from 101,601 subjects who were followed up with regard to cancer development through 1992. RESULTS: Among 208 gastric adenocarcinoma cases, we found a strong positive association between H. pylori infection and non-cardia gastric cancer (odds ratio (OR), 5.15; 95% confidence interval (CI), 2.83-9.37), and a statistically significant negative association with cardia cancer (OR, 0.40; 95% CI, 0.20-0.77). Adjustment for socioeconomic factors and smoking did not materially alter the effect estimates. The association between the infection and non-cardia cancer was stronger for tumors distal to the angulus and tended to be stronger in women than in men. The results were similar across Laur?n morphologic subtypes. CONCLUSIONS: These results strengthen the evidence of H. pylori infection as a risk factor in non-cardia gastric cancer. A negative association with H. pylori infection was found for cardia cancer.