The objective of our study was to assess whether high-fidelity simulation-based training is more effective than traditional didactic lecture to train radiology residents in the management of contrast reactions. This was a prospective study of 44 radiology residents randomized into a simulation group versus a lecture group. All residents attended a contrast reaction didactic lecture. Four months later, baseline knowledge was assessed with a written test, which we refer to as the "pretest." After the pretest, the 21 residents in the lecture group attended a repeat didactic lecture and the 23 residents in the simulation group underwent high-fidelity simulation-based training with five contrast reaction scenarios. Next, all residents took a second written test, which we refer to as the "posttest." Two months after the posttest, both groups took a third written test, which we refer to as the "delayed posttest," and underwent performance testing with a high-fidelity severe contrast reaction scenario graded on predefined critical actions. There was no statistically significant difference between the simulation and lecture group pretest, immediate posttest, or delayed posttest scores. The simulation group performed better than the lecture group on the severe contrast reaction simulation scenario (p = 0.001). The simulation group reported improved comfort in identifying and managing contrast reactions and administering medications after the simulation training (p ≤ 0.04) and was more comfortable than the control group (p = 0.03), which reported no change in comfort level after the repeat didactic lecture. When compared with didactic lecture, high-fidelity simulation-based training of contrast reaction management shows equal results on written test scores but improved performance during a high-fidelity severe contrast reaction simulation scenario.