The scaffold attachment factors SAFB1 and SAFB2 have been shown to function as estrogen receptor (ERalpha) co-repressors in breast cancer cells, and to affect many cellular processes such as stress response, RNA processing, and apoptosis. SAFB1 and SAFB2 have also been implicated in breast tumorigenesis: Their shared chromosomal locus at 19p13 is frequently lost in breast cancer, mutations have been identified, and overexpression results in growth inhibition. The purpose of this study was to determine SAFB1/SAFB2 protein expression in human breast tumors, to correlate their expression with either natural progression ("prognostic factor") or with response to Tamoxifen ("predictive factor"), and to analyze potential correlations with tumor characteristics. SAFB1/SAFB2 protein were measured by immunoblotting using a pan-SAFB antibody in tumor extracts from patients with long-term clinical follow-up (n = 289), a subset of whom had received no adjuvant systemic therapy after breast cancer surgery (n = 117) and another subset of whom were treated with adjuvant Tamoxifen (n = 172). SAFB levels were correlated with clinico-pathological variables and patient outcome. SAFB levels varied widely, with 25 tumors not expressing detectable levels of SAFB. SAFB expression was significantly correlated with ERalpha, HER-2, bcl-2 and with expression of other ERalpha coregulators such as SRC-3. There was no association between SAFB expression and disease free survival, however, low SAFB expression was significantly associated with worse overall survival in patients who did not receive adjuvant therapy. This study shows that low SAFB protein levels predict poor prognosis of breast cancer patients, suggesting critical functions of SAFB1 and SAFB2 in breast cancer cells.