Powerful inhibitors of acetylcholinesterase (phospholine iodide, paraoxon, and Soman) were used either separately or in combination with an anesthetizing drug (nembutal), an acetylcholine antagonist (atropine sulfate), or a convulsive drug (metrazole) to study the resistance of the blood-brain barrier to their effects. On the basis of measurements of acetylcholinesterase inhibition in rat brain stem and corpus striatum, it was concluded that these anticholinesterase drugs increased the permeability of the blood-brain barrier, provided that seizures were manifested shortly after administration of these drugs. Rats that were treated prophylactically with either nembutal or atropine sulfate did not convulse and, consequently, damage to the blood-brain barrier integrity was reduced significantly, despite a high degree of acetylcholinesterase and butyrylcholinesterase inhibition. It is suggested that anticholinesterase drugs enhance brain AChE inhibition by inducing strong convulsions and, thereby, increase their own penetration through the blood-brain barrier. It does not appear likely that acetyl- or butyrylcholinesterase located in the walls of the brain capillaries is involved in maintenance of the blood-brain barrier.