Retinal and other tissue histamine synthesis is increased in experimental diabetes; histamine infusion causes blood-ocular barrier breakdown in nondiabetic rats. We have examined the hypothesis that antihistamines prevent blood-ocular barrier breakdown in streptozotocin diabetes using male Sprague-Dawley rats held 28 days. During the last 7 days they were divided into these treatment groups: control (C), untreated diabetic (D), diabetic rats receiving diphenhydramine-HCl (B), diabetic rats receiving ranitidine (R) and diabetic rats receiving diphenhydramine and ranitidine (BR). Vitreous albumin content was measured 6 hr following fluorescein isothiocyanate bovine serum albumin (FITCBSA) injection. Data show that D had a 98.3% increase in vitreous body FITCBSA over C (p less than 0.05) while B and R showed respective decreases of 34.9% and 51.4% compared to D, R being significantly lower than D (p less than 0.05). BR showed a decrease of 71% (p less than 0.05) compared to D, and R and BR groups were not significantly different from C (p less than 0.05). Leakage into the vitreous was from the retina, not the ciliary body. These data indicate that 1) experimental diabetes results in elevated blood-ocular barrier permeability, which can be reversed by diphenhydramine-HCl and ranitidine; and 2) histamine H1- and H2-receptor activation and interaction by altered endogenous histamine metabolism may mediate blood-ocular barrier breakdown, implicating a pathogenic role of histamine in diabetic retinopathy.