AIMS--To investigate the expression of pepsinogen A3 (Pg3) encoding genes in the gastric mucosa of normal controls and subjects with atrophic gastritis and gastric cancer. METHODS--One hundred and fifty nine patients underwent upper gastrointestinal endoscopy with sampling of gastric biopsy specimens and serum. Pg3 isoproteins were determined by electrophoresis in serum and gastric mucosal biopsy specimens. Pg3 encoding genes were assessed by PCR in DNA obtained from peripheral blood. RESULTS--One hundred and one subjects (82 normal histology/chronic gastritis, 17 atrophic gastritis, two gastric cancer) showed a pepsinogen phenotype with presence of Pg3 and a corresponding pepsinogen genotype with presence of Pg3 encoding genes. Fifty eight subjects showed a phenotype lacking Pg3. In 39 of them (23 normal histology/chronic gastritis, 11 atrophic gastritis, five gastric cancer), a corresponding genotype without Pg3 encoding genes was found. However, in the remaining 19 subjects (4 normal histology/chronic gastritis, nine atrophic gastritis, six gastric cancer); Pg3 encoding genes were demonstrable in the absence of Pg3 production. CONCLUSIONS--Unexpressed Pg3 encoding genes can be shown in many cases of atrophic gastritis and gastric cancer, but rarely in healthy controls and subjects with superficial gastritis. The correlation of atrophic gastritis and gastric cancer with a pepsinogen phenotype lacking Pg3 can be explained by loss of expression of Pg3 encoding genes throughout the complete gastric mucosa. The mechanism of such loss and the importance as a marker for premalignant degeneration have to be elucidated.