Background: Although modern contrast agents have tolerability superior to older agents, significant differences remain between the agents currently in use. Methods: To investigate the incidence of early (<24 hours) and late (>24 hours to 7 days) reactions to 3 contrast agents commonly used in cardiac catheterization, we performed a randomized, prospective, double-blind trial in which 2001 patients received one of the following agents: iopamidol 340, a nonionic monomer; ioxaglate 320, an ionic dimer; and iodixanol 320, a nonionic dimer. Possible reactions to contrast were recorded during the hospital admission and after discharge by means of a questionnaire, telephone follow-up, or both. Results: Early reactions occurred in 22.2% of those receiving ioxaglate, 7.6% of those receiving iodixanol, and 8.8% of those receiving iopamidol (P < .0001). Late skin reactions occurred in 12.2% of those receiving iodixanol, 4.3% of those receiving ioxaglate, and 4.2% of those receiving iopamidol (P < .0001). Conclusions: The early side effect profile of certain ionic contrast agents suggests that these agents should no longer be used routinely in cardiac catheterization. The use of nonionic agents, however, is associated with late skin reactions, but there are notable differences between the monomeric and dimeric compounds. Although the skin reactions are generally benign, this is not always the case. Patients should be advised accordingly.