To examine whether leukotrienes could increase blood-brain barrier permeability, rats were anesthetized and injected intravenously with Evans blue. Ten microliters of vehicle, of leukotrienes B4, C4, or E4, or of arachidonic acid was injected over 1 hour directly into the brain parenchyma. The percentage of the total surface area of Evans blue extravasation in a coronal section of brain centered on the injection site was then determined as an estimate of blood-brain barrier permeability. Leukotrienes B4, C4, and E4, and arachidonic acid all increased blood-brain barrier permeability, but this effect was lost when the total dose was reduced to 20 ng. Increased blood-brain barrier permeability induced by arachidonic acid could be prevented by pretreatment with the lipoxygenase inhibitor BW755C, but not with indomethacin. Leukotrienes may play a role in the development of increased blood-brain barrier permeability after cerebral injury.