This study was performed to assess the relative contributions of contrast medium osmolality and chemotoxicity to contrast-induced blood-brain barrier (BBB) damage. Experimental carotid angiography was carried out in rabbits with mannitol at an osmolality of 714 mOsm/kg, with the nonionic, monomeric contrast media iohexol and ioversol at similar osmolalities, and with the nonionic, dimeric contrast media iodixanol and iotrolan at osmolalities less than half that of the mannitol. The amount of damage caused by the procedure was assessed by determining the amount of intracerebral extravasation of intravascularly injected technetium-99m-pertechnetate. Mannitol caused no detectable BBB damage, but all four contrast media caused BBB damage that was significantly more severe than that caused by mannitol. The BBB damage caused by carotid angiography with iohexol, ioversol, iodixanol, and iotrolan was not attributable to their osmolalities, but due to some other physical and/or chemical effects of these media on the BBB.