Purpose To determine if the allergic-like breakthrough reaction rate of intravenous corticosteroid prophylaxis administered 5 hours before contrast material-enhanced computed tomography (CT) is noninferior to that of a traditional 13-hour oral regimen. Materials and Methods Institutional review board approval was obtained and informed consent waived for this retrospective noninferiority cohort study. Subjects (n = 202) who completed an accelerated 5-hour intravenous corticosteroid premedication regimen before low-osmolality contrast-enhanced CT for a prior allergic-like or unknown-type reaction to iodine-based contrast material from June 1, 2008, to June 30, 2016, were identified. The breakthrough reaction rate was compared by using the Farrington and Manning noninferiority likelihood score to test subjects premedicated with a traditional 13-hour oral regimen (2.1% [13 of 626]). All subjects were premedicated for a prior allergic-like or unknown-type reaction to iodine-based contrast material. A noninferiority margin of 4.0% was selected to allow for no more than a clinically negligible 6.0% breakthrough reaction rate in the cohort that received 5-hour intravenous corticosteroid prophylaxis. Results The breakthrough reaction rate for 5-hour intravenous prophylaxis was 2.5% (five of 202 patients; 95% confidence interval: 0.8%, 5.7%), which was noninferior to the 2.1% (13 of 626 patients; 95% confidence interval: 1.1%, 3.5%) rate for the 13-hour regimen (P = .0181). The upper limits of the confidence interval for the difference between the two rates was 3.7% (0.4%; 95% confidence interval: -1.6%, 3.7%), which was within the 4.0% noninferiority margin. All breakthrough reactions were of equal or lesser severity to those of the index reactions (two severe, one moderate, and one mild reaction). Conclusion Accelerated intravenous premedication with corticosteroids beginning 5 hours before contrast-enhanced CT has a breakthrough reaction rate noninferior to that of a 13-hour oral premedication regimen. © RSNA, 2017.