A series of 130 eyes with ocular melanomas, 19 normal eyes, and 18 eyes affected with other disorders leading to blood-ocular barrier (BOB) breakdown were immunohistochemically stained for albumin to localize sites of BOB failure within the retina, ciliary body, and iris. Thirty-nine of the eyes containing melanomas and all of the other eyes were also immunohistochemically stained for vascular endothelial growth factor (VEGF), to investigate its potential role as a mediator for BOB failure. Eyes with melanomas showed widespread leakage through the retinal pigment epithelium, and 58% demonstrated leakage from retinal vessels in the proximity of the tumor. BOB failure remote from the tumor also occurred in retina (50%), optic nerve head (77%), ciliary body (51%), and iris (51%), suggesting that a soluble mediator may be involved. VEGF was demonstrated intraretinally in the proximity of (46%) and remote from (24%) melanomas and in eyes affected by other disease processes, particularly those involving neoplasia or retinal detachments, usually within particular cell populations (ie, retinal vessel walls, ganglion cells, inner or outer nuclear layers, retinal pigment epithelium). VEGF localization in retina, ciliary body, and iris often coincided with sites of extravasated albumin. Preincubation of albumin or VEGF antibodies with normal serum or VEGF peptide, respectively, eliminated or markedly reduced all immunoreactivity. Only 1 of 14 normal postmortem eyes and 0 of 5 normal surgically removed eyes showed VEGF positivity in the retina, 5 of 19 normal eyes had weak positivity in the ciliary body, and VEGF was not demonstrated in the iris of normal eyes. VEGF cannot account for all of the BOB failure associated with ocular melanomas, but appears likely to play a contributing role in many cases.