Background: For subjects who had previous hypersensitivity (HSR) to low-osmolar contrast media (LOCM), changing contrast media is recommended. However, determining the safest alternative LOCM is uncertain. We investigated the cross-reactivity among LOCMs and the outcomes of re-exposure in patients with previous immediate HSRs. Methods: The outcomes of re-exposure were assessed in the cohort with previous LOCM-associated HSR by the skin testing results and the presence of a common N-(2,3-dihydropoxypropyl) carbamoyl side chain. Results: Among 431 patients with previous HSR who underwent 482 skin tests, 250 cases (51.9%) showed positivity to intradermal tests, which was positively associated with the severity of HSR. The cross-reactivity among LOCMs was higher between LOCMs sharing common side chain compared to those not sharing (21.5% vs. 13.3%, P = .008). The recurrent HSRs was significantly reduced from 46.6% on re-exposure to culprit LOCM to 12.3% with changing LOCM based on the skin test results (P = .004). The overall recurrence rate was not further reduced when the LOCM was changed based on presence or absence of common side chain (15.1% vs. 11.8%, P = .428). However, for those who had severe index HSRs, skin test non-reactive LOCMs exposures, without the common side chain, resulted in a significant reduction in recurrent HSRs compared to LOCMs with the common side chain (24.0% vs. 7.8%, P = .049). Conclusion: In patients who experienced a severe index HSR to LOCM, avoidance of re-exposure to LOCMs with a common side chain or a positive skin test result is safer.