In a pilot study involving 235 patients we previously showed that the urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 were associated with a poor response to tamoxifen therapy in recurrent breast cancer (J Natl Cancer Inst 87 [1995] 751-756). The present study involves 534 patients who were treated with tamoxifen as first-line therapy for metastatic disease. The overall response rate was 51% (objective response: 15%, no change > 6 months: 36%). In these patients we have evaluated the predictive value of uPA, its receptor uPAR, and its inhibitors PAI-1 and -2. The parameters were measured in cytosols with ELISA. In univariate analysis for progression-free survival (PFS) using continuous variables, ER and PgR were related with a favorable outcome, while uPA, uPAR and PAI-1, were associated with a poor response to therapy and a poor PFS (all: P < 0.01). PAI-2 was not significantly related with response or PFS in univariate analysis. In multivariate analysis for PFS, using dichotomized variables (in addition to a basic model including age and menopausal status, disease-free interval, site of metastasis, ER and PgR), each factor when added separately contributed to the model. The relative hazard rate (RHR) for PAI-2 was 0.8, while for uPA, uPAR and PAI-1, the RHR varied from 1.23 to 1.35 (all: P < 0.05).