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The aim of this study was to determine the severity of breakthrough reactions to gadobenate dimeglumine in patients premedicated with a 13-hour premedication regimen.Institutional review board approval was obtained and informed consent waived for this Health Insurance Portability and Accountability Act–compliant retrospective cohort study. All acute allergic-like reactions to gadobenate dimeglumine from 11/1/2008 to 1/31/2016 were identified. Of these, 19 allergic-like reactions followed 13-hour premedication: 150 mg prednisone and 50 mg diphenhydramine (ie, “breakthrough reactions”). Reasons for premedication, risk factors, index reaction characteristics, and breakthrough reaction characteristics were catalogued. Reaction severities were assigned using American College of Radiology guidelines. Severities of breakthrough (n = 19) and nonbreakthrough reactions (n = 97) were compared with the Cochran-Armitage test for trend.Premedication was most commonly given (63% [12/19]) for a previous allergic-like reaction to gadolinium-based contrast material (GBCM); in 37% (7/19), it was given for a different risk factor. In those premedicated for a previous allergic-like reaction to GBCM of known severity (n = 9), the breakthrough reaction severity was the same as index reaction severity in 56% (5/9), less severe in 11% (1/9), and of greater severity in 33% (3/9). Two severe breakthrough reactions occurred; both were in subjects premedicated for risk factors other than a previous GBCM reaction. No subjects died. Five subjects were reexposed to GBCM a total of 9 times; no repeat breakthrough reactions occurred. Breakthrough reactions were more severe than nonbreakthrough reactions (P = 0.046), but the level of significance was borderline.Premedication does not eliminate severe reactions to gadobenate dimeglumine. Breakthrough reactions to gadobenate dimeglumine can be of greater severity than index reactions.