Mesothelioma has not been commonly reported as a cause of hypercalcemia of malignancy. We have studied a patient with malignant mesothelioma and hypercalcemia in association with elevated plasma concentrations of parathyroid hormone-like peptide (PLP). Immunohistochemical analysis of the tumor and seven of eight other mesotheliomas that were not associated with hypercalcemia revealed the presence of PLP cytoplasmic immunopositivity. PLP immunopositivity was also detected in normal and reactive mesothelial cells. The results of these studies suggest that PLP immunoreactivity is common in normal and neoplastic mesothelial cells and raises the possibility that PLP production may play a role in the pathogenesis of hypercalcemia associated with mesothelioma.