In intravascular application of radiographic contrast media causes hypersensitivity reactions, in which histamine release may play a major role. We examined the interaction between contrast medium and morphine. Among the four nonionic contrast media examined, iopamidol showed the most marked histamine release from rat peritoneal mast cells in vitro. Although iopamidol and morphine themselves did not induce histamine release at concentrations up to 65 mgI/ml and 3 mM, respectively, their combination resulted in a significant histamine release. These findings suggest that patients with exposure to medicines that induce histamine release may have a higher incidence and severity of hypersensitivity reactions to radiographic contrast media.