None of the established prognostic factors in breast cancer (BC) is able to determine the final outcome with certainity. Tumor biological factors involved in tumor invasion and metastasis, such as cathepsins and proteins of u-PA system, have been put forward in the recent literature as strong novel prognostic factors in BC. We therefore evaluated prognostic and predictive value of cathepsin-D (CD) and cathepsin-L (CL) in 715 operable BC patients. CD and CL were determined in tumor extracts using immunoradiometric and ELISA assays, respectively. During follow-up (median 37 months), 151 (21%) patients relapsed. In a multivariate analysis of disease-free survival (DFS), CL (p=0.04), nodal status (p<0.001) and hormone receptor status (p<0.001) were the only independent significant prognostic factors. CL thus provided independent prognostic information on DFS and could also predict a response to adjuvant chemotherapy (ChT), while CD had no significant prognostic and predictive impact.