Background: Intravenous (IV) iron therapy is performed in community practices and hospitals with modern formulations when oral administration becomes impractical. Effective replacement of iron is important for the treatment of iron deficiency and anemia. Can IV iron be rechallenged in individuals with a history of adverse reactions? This review is to explore the challenge of this, when clinically indicated. Methods: After performing a literature search, five studies (combined total sample number=1,006) for re-exposure of IV iron to individuals with a history of past reactions were identified, observed, and analyzed. Re-exposure included reactions ranging from mild to moderate and few cases of severe type. Results: The majority (>80%) of IV iron rechallenges were tolerable, safe, and successful without major serious incidents. There were no reports of major reactions (severe hypersensitivity reactions or anaphylaxis) in these re-exposures. Conclusion Re-administration of IV iron therapy in patients with a previous adverse reaction is plausible, with benefit and risk stratification. A rechallenge would depend on the nature and degree of the adverse reaction and use of alternative formulations. Rechallenge to a previous severe hypersensitivity reaction or anaphylaxis with the same product has not been reported in these studies. Evidence on the benefit of premedication use is conflicting and requires further studies.