Background: Obesity and physical inactivity are associated with breast cancer recurrence and mortality. The mechanisms explaining these associations are not fully understood. Vascular Endothelial Growth Factor (VEGF) is an essential component in angiogenesis, common to both tumor vascularization and adipose tissue expansion. VEGF levels have been found to be elevated in the serum of women with breast cancer and associated with a poorer prognosis. This study looked at VEGF changes in breast cancer survivors participating in either a weight loss study or an exercise study. We hypothesized that weight loss would be correlated with decreased VEGF levels compared to exercise alone. Methods: We examined changes in serum VEGF in two randomized trials in overweight breast cancer survivors: a diet-induced weight loss trial of 100 women randomized to a weight loss and exercise counseling intervention with either telephone or in-person counseling (n = 67) or usual care (n = 33), and a supervised exercise trial in which 121 women were randomized to aerobic exercise (n = 61) or usual care (n = 60). Body composition (height, weight, and DEXA scans), physical activity and diet were measured at baseline and 6-months. Fasting blood samples were collected at baseline and 6 months. We compared mean baseline to 6-month between groups using a general linear regression model. Results: In the weight-loss trial, the weight loss group had a 6% weight loss and a 5.0% decrease in VEGF (mean ± 95% CI -16.4 pg/ml ± 9.2) while the usual care group had a 2% weight loss and a 4.8% increase in VEGF (12.5 pg/ml ± 11.7), p = 0.05 between groups. In the exercise trial, no significant weight loss was observed in either group. The change in VEGF from baseline to 6 months did not differ by randomization group. The 6 month change in the exercise group was 1.4 ± 6.8 (0.5% increase) and usual care group was 12.6 ± 7.3 (4.6% increase), p = 0.27 between groups. Conclusions: VEGF decreased in breast cancer survivors randomized to a weight loss intervention but did not change in those participating in an exercise only trial. Weight loss may play a larger role in mediating changes in VEGF compared to exercise alone.