The objective of this study was to review the investigation that uncovered the medical mystery of burn patients developing unexpected renal failure. The authors examined published and unpublished manuscripts and case reports, as well as conducted personal interviews with primary sources. In the late 1970s, emergence of resistant bacterial strains to the topical antimicrobial silver sulfadiazine occurred at the University of Virginia Medical Center. In the search for an alternative topical antimicrobial with known coverage of Pseudomonas aeruginosa, Furacin Soluble Dressing was substituted. However, Furacin Soluble Dressing produced an unexpected toxicity syndrome of hyperosmolality, metabolic gap acidosis, hypercalcemia, and ultimately renal failure. In a search for an antimicrobial with an improved spectrum against Pseudomonas, a Federal Drug Administration-approved product was used to treat large surface area burns. An unexpected toxicity syndrome developed which was traced to the polyethylene glycol base of Furacin Soluble Dressing. This substance was absorbed through the burn wounds, metabolized, and resulted in a toxicity syndrome leading to renal failure. The burn community should be cautious when using products that may be approved as nontoxic for small surface area application, as they may have unexpected medical side effects when used with large surface area burns.