The structure and function of the blood-brain barrier (BBB) is determined mainly by the characteristics of brain capillary endothelial membranes. Lipophilic drugs that modify the cell membrane might be anticipated to alter the BBB. We investigated the effect of acute ethanol in combination with either a barbiturate or a non-barbiturate anesthetic on the ability of the rat BBB to exclude circulating horseradish peroxidase (HRP). Rats were injected into the peritoneal cavity with ethanol plus either a barbiturate (pentobarbital) or a non-barbiturate (ketamine hydrochloride) anesthetic. HRP was subsequently injected transcardially 30 s prior to decapitation. In the ethanol plus barbiturate-treated rats focal leakage of HRP caused peroxidase levels in the cerebral cortex to be about 8-fold higher than in ethanol plus ketamine hydrochloride-treated rats. Ultrastructurally endothelial cells in leaking vascular segments were infiltrated with HRP and, in some cases, they were lysed so that the structural integrity of the blood-brain interface was lost. Lysed segments were accompanied by staining of the adjacent basal lamina with HRP, and edematous astrocytic endfeet. These results show that ethanol plus a barbiturate anesthetic causes breakdown in the BBB by structurally damaging brain capillary endothelial cells. Whether the damage is caused by the expansion and lysing of the cell membrane by these two lipophilic drugs, or by increased intracellular calcium to toxic levels is not yet known.