We have used immunohistochemistry to evaluate the clinicopathological significance of hepatocyte growth factor (HGF) and Met/HGF receptor expression in ductal lesions of 46 human pancreata. Normal duct epithelium shows no significant immunoreactivity for either HGF or Met. Strong immunostaining for HGF was respectively demonstrated in hyperplastic and severely dysplastic epithelia in 35.5 and 40% of cases with such duct lesions, whereas 37% of ductal adenocarcinoma showed diffuse HGF immunostaining. Positive Met immunostaining was demonstrated in 58, 80, and 78%, respectively, of specimens demonstrating the above duct lesions. Patients with resectable ductal adenocarcinoma demonstrating diffuse Met immunostaining have a significantly longer survival than those with tumors showing negative/focal staining (19.7 versus 8.1 months at P = 0.026). In contrast, HGF immunoreactivity did not significantly correlate with the survival of the patients. The results suggest that HGF and Met expression may play significant bifunctional roles during human pancreatic ductal carcinogenesis and progression. Whereas an upregulation of Met receptor expression and HGF-Met interaction may have an important pathogenetic role during the early stages of neoplastic promotion, a lack or subsequent loss of Met expression in invasive adenocarcinoma appears to result in a more aggressive clinical behavior.