The capacity of conventional and new low-osmolality contrast agents to stimulate histamine release from human basophils has been studied in vitro. When compared on an iodine concentration basis, the new agents release less histamine than the conventional agents at intermediate and higher concentration. However, the newer compounds exhibit a biphasic histamine release response to increasing iodine concentration with a low concentration peak, a phenomenon not previously described. Among the conventional ionic agents, meglumine salts were confirmed to be more potent histamine releasers than sodium salts. Possible mechanisms of this histamine release and the bearing of the findings on the safety of contrast media are discussed.