The prognostic value of tumour-associated proteolysis, especially the urokinase plasminogen activator (uPA) system, has been proposed in gastric cancer. In a prospective series of 203 resected patients, the expression of immunohistochemically assessed uPA, uPA-receptors and PAI-1 was strongly associated with survival. Multivariate analysis revealed PAI-1 as a new independent prognostic factor (overall survival: P = 0.005, relative risk 1.47, 95% CI 1.31-1.64). Gastric cancer is assumed to consist of two biologically different tumour types according to the histomorphological Lauren's classification. Consideration of this classification revealed strong prognostic impact of the uPA system in diffuse type cancers (overall survival: uPA, P = 0.028, relative risk 1.58, 95% CI 1.30-1.91; uPA-receptor, P = 0.001, relative risk 1.42, 95% CI 1.25-1.61) which are by definition low-differentiated (G3). For intestinal type cancers only in low-differentiated (G3) tumours a prognostic value was obtained (overall survival: PAI-1, P = 0.050, relative risk 2.16, 95% CI 1.17-3.96) while the association of grading and survival was not significant. This implies that the clinically relevant impact of the uPA system is associated with tumour differentiation.