Serum and plasma concentrations of vascular endothelial growth factor (sVEGF and pVEGF), serum concentrations of interleukin 6 (IL-6), and VEGF platelet load (VEGF/pl) in the blood of healthy controls (n = 26), breast cancer patients with locoregional disease (n = 31), and patients with progressive advanced disease (n = 73) have been compared. The 95th percentile values for the control population were 250 pg/mL for sVEGF, 30 pg/mL for pVEGF, and 1.6 pg/mL for IL-6. The 95th percentile value of the calculated VEGF/pl was 1.0 pg/10(6) platelets in the control population. Serum VEGF concentrations correlated with platelet number in all the groups. Patients with thrombocytosis had a median sVEGF concentration of 833 pg/mL, compared to 249 pg/mL in other patients (P = 0.018). Serum IL-6 levels correlated with sVEGF levels and with the calculated VEGF/pl. Serum IL-6 concentration was significantly higher in patients with breast cancer compared to healthy controls (P < 0.0001). Median IL-6 serum levels were nearly 10 times higher in patients with metastatic breast cancer as compared to the those with locoregional disease (6.0 pg/mL versus 0.7 pg/mL, respectively). Plasma VEGF and the VEGF/pl were also significantly different in the 3 groups. The ratio between sVEGF and pVEGF tended to be smaller in the metastatic breast cancer group compared to the patients with locoregional disease (median, 7.5 versus 10.1, respectively; P = 0.066), suggestive of more intravasal platelet degranulation in the former group. Serum IL-6 level is the most discriminative factor separating healthy controls and the locoregional and metastatic breast cancer patient groups. These results suggest a role for tumor-derived IL-6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF.