Parathyroid hormone-related protein (PTHrP) is an important humoral factor in the syndrome of humoral hypercalcaemia of malignancy (HHM) and its importance is evident by the many studies examining either PTHrP mRNA expression, intracellular peptide, or circulating PTHrP levels in patients with malignancy. However, the relationship between PTHrP mRNA expression, intracellular localization of peptide, and circulating PTHrP levels in the same group of patients with malignancy has not been examined. This study was carried out to explore this relationship in a group of patients with solid tumours associated with either normocalcaemia or hypercalcaemia. PTHrP mRNA and peptide were localized by in situ hybridization and immunohistochemistry respectively in 26 squamous carcinomas and 15 adenocarcinomas from patients who were either hypercalcaemic or normocalcaemic. Plasma PTHrP1-86 and serum PTH1-84 concentrations were measured by two-site immunoradiometric assays. PTHrP mRNA and peptide were localized in 11 (100 per cent) and 10 (91 per cent) of 11 squamous tumours from hypercalcaemic patients, all of whom had detectable circulating PTHrP levels, and in 14 (97 per cent) and 11 (73 per cent) respectively of 15 squamous tumours from normocalcaemic patients. PTHrP mRNA and peptide were localized in only two (28 per cent) and four (57 per cent) respectively of seven adenocarcinomas associated with hypercalcaemia. Since the majority of squamous tumours synthesized PTHrP irrespective of the calcium status of the patient, this suggests that the clinical expression of tumour-derived PTH-like bioactivity may depend on the rate of secretion of PTHrP rather than gene expression, and that the bioactivity of secreted PTHrP may be modulated by post-translational processing.