Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability. Many types of malignant human tumors have been shown to produce VEGF. Recently, increased serum concentrations of VEGF (S-VEGF) have been reported in patients with various types of cancer, and high S-VEGF levels have also been associated with unfavorable prognosis. We have now measured S-VEGF in sera taken from 105 patients with a benign breast tumor or breast cancer. None of the women with a benign breast tumor had S-VEGF higher than 328 pg/ml (median, 57 pg/ml) whereas S-VEGF levels in metastatic breast cancer ranged from 7 to 1347 pg/ml (median, 186 pg/ml; P = 0.0018), and in locoregional breast cancer from 11 to 539 pg/ml (median, 104 pg/ml; P = 0.13). S-VEGF was higher in patients with locoregional ductal cancer (median, 107 pg/ml) than in those with locoregional lobular cancer (median, 44 pg/ml; P = 0.029) or in patients with benign breast tumor (median, 57 pg/ml; P = 0.033). Patients with metastatic cancer undergoing therapy had lower S-VEGF than those who had symptomatic treatment only (P = 0.021). The results indicate that dissemination of breast cancer may be accompanied by an elevation of circulating VEGF and that primary ductal cancers are associated with higher S-VEGF levels than lobular cancers or benign breast lesions.