A total of 5,209 asymptomatic, middle-aged subjects, whose serum pepsinogen (PG) and Helicobacter pylori antibody levels had been assessed, were followed for 10 years. Subjects with positive serum H. pylori antibodies (>50 U/mL) had an increased cancer risk (HR 5 3.48, 95% CI 5 1.26-9.64). Risk of gastric cancer increased as the antibody level increased; the H. pylori-positive group with antibody levels >500 U/mL had the highest incidence rate (325/100,000 person-years). Cancer development also increased with a reduced serum PG I level or a reduced PG I/II ratio; the risk was significantly elevated with serum PG I level ≤30 ng/mL (HR 5 3.54, 95% CI 5 1.95-6.40) or PG I/II ratio ≤3.0 (HR 5 4.25, 95% CI 5 2.47-7.32). Furthermore, the risk of diffuse-type cancer increased as PG II level increased; it was significantly elevated with PG II level ≥30 ng/mL (HR 5 3.81, 95% CI 5 1.10-13.21). Using H. pylori antibody and PG levels, subgroups with an especially high or low cancer incidence rate could be identified. H. pylori-negative or indeterminate subjects with low PG level (PG I ≤30 ng/mL or PG I/II ratio ≤2.0) or H. pylori-positive subjects with antibody levels >500 U/mL and a low PG level were among the subgroups with a high cancer incidence rate (over 400/100,000 person-years). In contrast, H. pylorinegative subjects with a PG I level >70 ng/mL or a PG I/II ratio >3.0 had the lowest risk; none of these subjects developed cancer. Thus, serum PG levels and/or H. pylori antibody levels can be used to predict the risk of cancer in individuals with H. pylorirelated gastritis from the general population. ' 2008 Wiley-Liss, Inc.Key words: gastric cancer; pepsinogen; Helicobacter pylori; chronic atrophic gastritis; intestinal metaplasia Stomach carcinogenesis in high-risk populations, including the Japanese population, is believed to begin with chronic active inflammation of the stomach mucosa, proceeding to extensive atrophy together with intestinal metaplasia, then to dysplasia, and finally to cancer. 1 Currently, Helicobacter pylori (H. pylori) is considered a major factor in the establishment of the carcinogenic sequence in the stomach. 2-12 H. pylori-related gastritis usually starts in the antrum and expands proximally towards the body of the stomach. [13][14][15] During this process, both multifocal atrophy and intestinal metaplasia develop, eventually leading to chronic atrophic gastritis (CAG) with extensive intestinal metaplasia. Several studies dealing with endoscopic biopsies or chromoendoscopic testing found that the progression of CAG increases the risk for cancer. 12,[16][17][18][19][20] Thus, an accurate and reliable evaluation of the extent of CAG is considered to be important for identifying individuals at high risk of cancer. The diagnosis of CAG is based on histopathology of the stomach mucosa. However, gastric endoscopy with biopsy is an invasive test and inappropriate for mass population screening. In addition, since CAG together with intestinal metaplasia is a multifocal process, it is difficult to ac...