Helicobacter pylori infection has been suggested to be associated with an increased risk of gastric cancer, and low levels of serum pepsinogen I (PG I) have been linked to atrophic gastritis, which is a risk factor for gastric cancer. In Finland, 39,268 persons from 25 cohorts participated during 1968-1972 in a health examination survey and were followed for up to 13 years. A nested case-control study was performed on 84 stomach cancer patients identified from the Finnish Cancer Registry and 146 controls matched for age, sex, and municipality. Serum samples drawn at the baseline study were analyzed. An elevated level of serum anti-H. pylori immunoglobulin A (IgA) antibodies (a titer > or = 70) and a low serum PG I level ( < 49 micrograms/liter) were associated with an increased risk of gastric cancer. The odds ratios were 2.52 (95% confidence interval (CI) 1.14-5.57) for high IgA and 2.68 (95% CI 1.35-5.30) for low PG I. For high immunoglobulin G (IgG) ( > or = 700), the odds ratio was only 1.50 (95% CI 0.70-3.22). When both high IgA and low PG I were present, the odds ratio was 5.96 (95% CI 2.02-17.57). The association of H. pylori infection with cancer became stronger with longer follow-up times, whereas that of low PG I was strongest at shorter follow-up times. Our findings support the hypothesis that H. pylori infection is a prevalent and potentially preventable cause of gastric cancer. They stress the value of IgA antibody determinations and provide new evidence for a pathogenesis leading from prolonged infection through atrophic gastritis to gastric cancer.