Pre-treatment oestrogen receptor (ER) expression in breast cancer predicts for rate of response to endocrine therapy but not for the quality or duration of response (DofR). ER is known to be down-regulated by anti-oestrogens. This study has tested the hypothesis that the degree of down-regulation of ER and the ER-regulated marker bcl-2 are associated with the quality and duration of tamoxifen response. 80 patients with ER+ve breast cancer (H-score > 10) receiving primary tamoxifen (n = 51 Stage I-II elderly; n = 29 Stage III) underwent sequential tumour biopsies for immunocytochemical assessment of ER, bcl-2 and the proliferation marker MIB1. Median follow-up is 45 months. By 6-months on therapy three patients had attained complete response (CR), 27 partial response (PR); 44 static disease (SD) and six progression (PD) by UICC criteria. Greater decrease in ER and bcl-2 H-score from pre-treatment to 6 weeks (p = 0.035, p = 0.037) and ER and bcl-2 H-score from pre-treatment to 6 months (p = 0.058, p = 0.036) were significantly associated with better quality of response (CR/PR vs SD/PD). Greater 6-week and 6-month reduction in bcl-2 H-score (p = 0.041, p = 0.036) and 6-week reduction in MIB1 (p = 0.013) were significantly correlated with longer DofR. This study demonstrates that greater down-regulation of ER and the ER-regulated protein bcl-2 on primary tamoxifen are significantly associated with a better quality of response and bcl-2 and the proliferation marker MIB1 a longer duration of response in ER+ve breast cancer.