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Though 2-stage revision is considered the gold standard in North America for treatment of periprosthetic joint infection, complications can be associated with use of antibiotic-impregnated spacers. We present a unique case of drug reaction with eosinophilia and systemic symptoms syndrome in a patient with retained antibiotic-impregnated spacer placed for the treatment of a periprosthetic joint infection. Although drug reactions in general are common, severe drug reactions like the one described in this article are exceedingly rare. After discontinuation of intravenous antibiotics and the initiation of corticosteroids, the patient’s symptoms resolved, despite retention of the spacer. Steroid administration and supportive care may result in resolution of symptoms without the need for surgical intervention for spacer removal. Keywords: Periprosthetic infection, Antibiotic spacer, Drug reaction, Two-stage revision