Secondary lymphedema is a common post-cancer treatment complication but the pathomechanisms underlying the disease remain unclear. Using a mouse-tail lymphedema model, we found an increase in local and systemic levels of the lymphangiogenic factor VEGF-C, and identified CD68+ macrophages as a cellular source. Surprisingly, overexpression of VEGF-C in a transgenic mouse model led to aggravation of lymphedema with increased immune cell infiltration and vascular leakage in comparison to wild-type littermates. Conversely, blockage of VEGF-C by overexpression of soluble VEGFR3 reduced edema development, diminishing inflammation and blood vascular leakage. Similar findings were obtained in a hind limb lymph node excision lymphedema model. Flow cytometry analyses and immunofluorescence stainings in lymphedematic tissue revealed that VEGFR3 expression was restricted to lymphatic endothelial cells. Our data suggest that endogenous VEGF-C causes blood vascular leakage and fluid influx into the tissue, thus actively contributing to edema formation. These data may provide the basis for future clinical therapeutic approaches.