Parathyroid hormone-related peptide (PTHrP) is a major factor in the pathophysiology of hypercalcaemia of malignancy. Recent evidence suggests that PTHrP may play an important role in the growth and differentiation of neoplastic as well as non-neoplastic cells. PTHrP was originally detected in normal fetal, but not adult, liver. We have used immunocytochemistry to show that reactive human bile ductules expressing a neuroendocrine phenotype contain immunoreactive PTHrP. These observations raised the possibility that PTHrP immunoreactivity may be useful in the differential diagnosis of primary liver tumours and metastases of adenocarcinoma. A total of 24 primary liver tumours and 22 metastases of adenocarcinoma were studied. All cholangiocarcinomas showed immunopositivity for PTHrP and chromogranin A, while all hepatocellular carcinomas were negative for PTHrP and showed only focal and weak positivity for chromogranin A. Mixed types of primary liver tumour contained PTHrP immunoreactivity only in the areas of cholangiocellular differentiation. Moreover, all metastatic adenocarcinomas were negative for PTHrP and chromogranin A except for two out of five metastatic breast adenocarcinomas. These two patients had bone metastases and hypercalcaemia and thus did not yield differential diagnostic problems with cholangiocarcinoma. None of the patients with cholangiocarcinoma and hepatocellular carcinoma had hypercalcaemia. We conclude that PTHrP is a useful marker for primary cholangiocarcinoma, especially in the differential diagnosis of hepatocellular carcinoma and metastatic adenocarcinoma.