Vascular leakage contributes to numerous disorders but only a limited number of molecules have been demonstrated to modulate permeability of the vessel wall. The vascular endothelial growth factor (VEGF) is a potent inducer of vascular leakage. Previous studies demonstrated that exogenous administration of placental growth factor (PlGF), a homologue of VEGF, stimulates vascular permeability but the role of endogenous PlGF in plasma extravasation during pathological conditions remains unknown. We recently generated PlGF deficient (PlGF(-/-)) mice and demonstrated that loss of PlGF impaired pathological angiogenesis by attenuating the response to VEGF. Here, we demonstrate that absence of PlGF reduces vascular leakage induced by skin wounding, allergens, and neurogenic inflammation. These findings suggest that inhibition of PlGF might be an attractive tool to reduce vascular leakage in various diseases.