The use of lower osmolality radiocontrast media (RCM) has been associated with satisfactory radiographic opacification and a reduced incidence of severe reactions. The higher cost without clearly established benefit of these media have limited their use. This investigation assessed the incidence of immediate generalized reactions (IGRs) to repeated RCM IGRs in pretreated high-risk patients who received iopamidol or iohexol during 200 procedures (181 intravascular). All patients had experienced a previous IGR to a conventional RCM. Pretreatment consisted of prednisone, 50 mg, 13, 7, and 1 hour before the procedure and diphenhydramine, 50 mg, 1 hour before the procedure in 140 intravascular infusions. Ephedrine, 25 mg, 1 hour before the infusion was added to prednisone-diphenhydramine in 41 cases. Only one (0.7%) urticarial reaction occurred in 141 procedures with prednisone-diphenhydramine. No repeated IGR occurred with the three-drug regimen. The reaction rate after pretreatment with prednisone-diphenhydramine or prednisone-diphenhydramine-ephedrine and use of conventional contrast media during 800 intravascular procedures was 9.1%, and with pretreatment and lower osmolality contrast media in 181 intravascular infusions, it was 0.5% (chi 2 = 14.35; p less than 0.001). Lower osmolality contrast media should be the contrast media of choice for patients with a prior IGR to conventional contrast media. In addition, patients should receive prednisone-diphenhydramine-ephedrine or prednisone-diphenhydramine prophylaxis.