As there is experimental evidence to suggest that tamoxifen may exert an anti-angiogenic effect, the present study was designed to investigate the effect of primary tamoxifen on breast tumour angiogenesis. Fifty seven patients with large operable primary breast cancers were treated with tamoxifen (20 mg daily) for between three and six months prior to definitive surgery. Clinical response to treatment was assessed by serial ultrasound measurements of tumour volume and a responding tumour was defined as one in which there was a greater than 25% reduction in volume at the end of treatment. Patients underwent a wedge biopsy at diagnosis and definitive surgery on completion of tamoxifen, thus providing tumour sections before and after treatment. Microvessel counts (mvc) were performed following staining with the endothelial cell marker, antibody to Factor VIII, and changes in mvc were correlated with response. Forty three of 57 patients had tumours that responded to tamoxifen. There was no difference in pre-treatment mvc between non-responding and responding tumours. Post-treatment mvc was significantly higher in non-responding than responding tumours. There was a significant reduction in mvc in responding tumours following treatment with tamoxifen, and a significant increase in mvc was detected in non-responding tumours. A significant correlation was demonstrated between percentage change in mvc and percentage reduction in tumour volume. This is the first study to demonstrate a reduction in breast cancer angiogenesis in tumours that have responded to primary tamoxifen in the clinical setting.