Ovarian cancer accounts for more deaths worldwide than any other gynecologic malignancy. Despite advances in treatment, mortality rates have remained steady, underscoring the need for new therapeutic strategies. A significant challenge for current therapies is overcoming tumor immunosuppression, therefore the identification of immunosuppressive factors produced within the tumor microenvironment, and the ability to target these factors could enhance anti-tumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which binds with high affinity to CD1d molecules, thereby suppressing NKT cell activation. In addition to GD3, we have identified vascular endothelial growth factor (VEGF) as an immunosuppressive factor secreted by ovarian cancers. Importantly, the level of VEGF in ovarian cancer serum and ascites fluid has been reported to directly correlate with disease burden, and is inversely correlated with survival. We found that VEGF inhibition results in decreased GD3 levels in human ovarian cancer cell lines and a concomitant restoration of NKT cell responses. To determine the mechanism by which VEGF signaling induces GD3 shedding by ovarian cancer cells and to elucidate the effect of VEGF on NKT cell function in vivo, we utilized the ID8 ovarian cancer mouse model. We found that ID8 cells overexpressing VEGF (ID8-VEGF) shed higher levels of GD3, and tumor-associated lymphocytes from ID8-VEGF tumor-bearing mice have decreased immune function. In good agreement with our preclinical studies, we found that higher VEGF levels in the ascites of ovarian cancer patients correlates with decreased immune cell function in lymphocytes isolated from both the tumor microenvironment and the periphery.  These data indicate that ovarian cancers may use VEGF to inhibit NKT cell responses as an early mechanism of tumor immune evasion, and suggest that targeting the VEGF/GD3 pathway may have a significant impact on anti-tumor immune responses.