The vasomotor effects of contrast media (CM), ioxilan, iohexol, and diatrizoate, and their isoosmotic sucrose solutions as controls, were studied in vitro in rings of thoracic aortas of rabbits. When the osmotic pressure of CM or controls reached the region of 380 mOsm/kg, vasoconstriction developed, reaching a maximum in about 1 hour; it was reversible. It could not be blocked by phentolamine, and therefore did not involve alpha-adrenoceptors. When added to aortic rings precontracted with noradrenaline, all of the CM produced vasodilatation, while reactions to sucrose varied. When endothelium was removed, CM still produced vasodilatation, suggesting a direct chemotoxic effect on smooth muscle. The dilatation effect does not involve the muscarinic receptors, beta-adrenoceptors, or stimulation of prostacyclin synthesis, since the vasodilator response was not blocked by atropine, propranolol, or indomethacin. Blockage of calcium channels did not appear to be a contributing factor. Since the dilator response to all CM was augmented in the presence of the phosphodiesterase inhibitor, iso-butylmethylxanthine (IBMX), it is likely that CM produce vasodilatation chemotoxically by activating the production of a cyclic nucleotide.