OBJECTIVE Our evaluation of a patient with a parathyroid hormone-related protein (PTHrP)-producing gastric adenocarcinoma and hypercalcemia prompted us to study the expression of PTHrP in 13 additional patients with gastric cancer and in 10 control cases. Our objective was to investigate by immunohistology the expression of PTHrP in gastric cancer. METHODS Immunohistology studies were conducted with two murine monoclonal antibodies to synthetic peptides of human PTHrP, 9H7, and 8B12. The 9H7 antibody was raised to the carboxy-terminal amino acid fragment (109-141) of PTHrP, and the 8B12 antibody was raised to the amino-terminal amino acid fragment (1-34) of PTHrP. RESULTS Paraffin-embedded tumor specimens from 13 of 14 cases of gastric adenocarcinoma stained positively with the antibody to the carboxy terminus of the PTHrP peptide, but none stained positively with the antibody directed against the amino terminus. None of 10 control cases stained positively with either antibody. The staining was predominately evident in the cytoplasm of the tumor cells. Except for the sentinel case, none of the other patients with gastric adenocarcinoma had hypercalcemia. Thus, gastric adenocarcinoma seems to rarely result in systemic hypercalcemia. CONCLUSIONS Our studies demonstrated that abnormal PTHrP production can occur in malignant cells without producing hypercalcemia. PTHrP may play a role in the pathogenesis of gastric adenocarcinoma that is independent of its hypercalcemic effects. PTHrP measurements may be clinically valuable in patients with cancer who are not hypercalcemic.