Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and is important to carcinogenesis. Previous studies relating circulating levels of VEGF to breast cancer have been limited by small numbers of participants and lack of adjustment for confounders. We studied the association between serum VEGF and breast cancer in an unmatched case-control study of 407 pre- and postmenopausal women (n = 203 cases, n = 204 controls). Logistic regression was used to model the breast cancer risk as a function of natural log transformed VEGF levels adjusted for age, Gail score, education, physical activity, history of breastfeeding, serum testosterone, and hormone therapy (HT) use. The majority of the population was postmenopausal (67.6%) and the average age was 56 years; age and menopausal status were similar among cases and controls. Geometric mean VEGF levels were non-significantly higher in cases (321.4 pg/ml) than controls (291.4 pg/ml; p = 0.21). In a multivariable model, the odds of breast cancer was 37% higher for women with VEGF levels > or =314.2 pg/ml compared to those with levels below 314.2 pg/ml, albeit not significantly (p = 0.16). There was no interaction between VEGF and menopausal status (p = 0.52). In this case-control study, VEGF was not significantly associated with breast cancer risk in pre- and postmenopausal women.