BACKGROUND In posterior uveitis the blood-retinal barrier (BRB) plays an important role in the pathogenesis of the disease. However, the morphologic correlate of BRB breakdown and the route of leukocyte migration remain poorly defined. METHODS Using an experimental model of autoimmune uveoretinitis in the rat, we have examined the ultrastructural alterations and leukocyte interactions occurring at the BRB. By employing electron-dense tracers, the development of BRB breakdown, and the route of extravasation were investigated. RESULTS No increase in BRB permeability was found before lymphocytic infiltration. At day 10 postimmunization with retinal-soluble antigen and beyond, inflammatory cells could be seen within the retina that was quickly followed by an extensive increase in the permeability of the retinal vasculature to lanthanum and horseradish peroxidase. Occasionally, horseradish peroxidase reaction product could be seen extending throughout the 'tight junctions' of the retinal endothelia, but not those of the retinal pigment epithelia. Inflammatory cells, particularly mononuclear cells, were seen forming perivascular cuffs and extending posteriorly towards the outer retina. Retinal damage was initially restricted to the outer nuclear and photoreceptor layers that were in close proximity to these vessels. Leukocytes could be seen adhering to the retinal vessels and penetrating the endothelial cell cytoplasm close to tight junctions, but were never seen probing the junctions directly. At the retinal pigment epithelium, however, there was little evidence of migration into the retina during the early stages of the disease, even though the choroid often became packed with inflammatory cells. At later stages, occasional inflammatory cells could be seen between, and apparently within, retinal pigment epithelium cells in areas overlying sites of severe choroidal infiltration. CONCLUSIONS The prime site of leukocyte infiltration and damage to the BRB in autoimmune uveoretinitis occurred at the level of the vascular endothelia and that diapedesis takes place primarily via an intraendothelial process.