The erbB-4 gene encodes a detected receptor protein that possesses intrinsic tyrosine kinase activity and belongs to the family of the epidermal growth factor receptor (EGFR); erbB-4 is stimulated by the heregulins and betacellulin, which enables this receptor to form heterodimers with erbB-2, a prerequisite for erbB-2 activation. Because the expression of erbB-4 mRNA is generally low in the pancreas, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine the erbB-4 levels in human normal and cancerous pancreatic tissue. Our results show that the mRNA expression of this receptor is 6-fold decreased in the non-metastatic stages of pancreatic cancer when compared to tumors with lymph node or distant metastases or to the normal pancreas. In addition, immunohistochemistry demonstrated that in the normal pancreas, the erbB-4 antigen was predominantly present in the cell membrane and cytoplasm of the ductal and acinar cells and at a much lower level, in islet cells. In pancreatic cancer, 61 of 75 samples exhibited weak to moderate immunoreactivity for erbB-4 in the tumor cells. Moreover, in the peri-tumorous region with chronic pancreatitis-like morphological changes, there was weak-to-moderate erbB-4 immunostaining in small ductules and degenerating acinar cells. Uni- and multivariate survival analyses using as variables age, sex, stage of cancer, histo-pathological grading, and erbB-4 immunoreactivity, revealed a significant effect for stage of cancer (p < 0.01) whereby the risk of dying was 2.3 times higher in patients with metastases than in patients without. However, the level of erbB-4 immunoreactivity in pancreatic cancer cells had no influence on patient survival.