Breakdown of the blood‐retinal barrier (BRB) occurs in several retinal diseases and is a major cause of visual loss. Vascular endothelial growth factor (VEGF) has been implicated as a cause of BRB breakdown in diabetic retinopathy and other ischemic retinopathies, and there is evidence to suggest that other vasopermeability factors may act indirectly through VEGF. In this study, we investigated the effect of several receptor kinase inhibitors on BRB breakdown resulting from VEGF, tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), insulin‐like growth factor‐1 (IGF‐1), prostaglandin E1 (PGE₁), or PGE₂. Inhibitors of VEGF receptor kinase, including PKC412, PTK787, and SU1498, decreased VEGF‐induced breakdown of the BRB. None of the inhibitors blocked leakage caused by TNF‐α, IL‐1β, or IGF‐1 and only PKC412, an inhibitor of protein kinase C (PKC) as well as VEGF and platelet‐derived growth factor (PDGF) receptor kinases, decreased leakage caused by prostaglandins. Since the other inhibitors of VEGF and/or PDGF receptor kinases that do not also inhibit PKC had no effect on prostaglandin‐induced breakdown of the BRB, these data implicate PKC in retinal vascular leakage caused by prostaglandins. PKC412 may be useful for treatment of post‐operative and inflammatory macular edema, in which prostaglandins play a role, as well as macular edema associated with ischemic retinopathies. © 2003 Wiley‐Liss, Inc.