Prostate-specific antigen (PSA) is a serine protease which may play a role in a variety of cancer types, including breast cancer. In the present study, we evaluated whether the level of PSA in breast tumour cytosol could be associated with prognosis in primary breast cancer, or with response to tamoxifen therapy in recurrent disease. PSA levels were determined by enzyme-linked immunosorbent assay (ELISA) in breast tumour cytosols, and were correlated with prognosis in 1516 patients with primary breast cancer and with response to first-line tamoxifen therapy in 434 patients with recurrent disease. Relating the levels of PSA with classical prognostic factors, low levels were more often found in larger tumours, tumours of older and post-menopausal patients, and in steroid hormone receptor-negative tumours. There was no significant association between the levels of PSA with grade of differentiation or the number of involved lymph nodes. In patients with primary breast cancer, PSA was not significantly related to the rate of relapse, and a positive association of PSA with an improved survival could be attributed to its relationship to age. In patients with recurrent breast cancer, a high level of PSA was significantly related to a poor response to tamoxifen therapy, and a short progression-free and overall survival after start of treatment for recurrent disease. In Cox multivariate analyses for response to therapy and for (progression-free) survival, corrected for age/menopausal status, disease-free interval, site of relapse and steroid hormone receptor status, PSA was an independent variable of poor prognosis. It is concluded that the level of PSA in cytosols of primary breast tumours might be a marker to select breast cancer patients who may benefit from systemic tamoxifen therapy.