BACKGROUND: Acetaminophen toxicity is common in clinical practice. In recent years, several European countries have lowered the treatment threshold, which has resulted in increased number of patients being treated at a questionable clinical benefit. OBJECTIVE: The primary objective of this study is to estimate the cost and associated burden to the United States (U.S.) healthcare system, if such a change were adopted in the U.S. METHODS: This study is a retrospective review of all patients age 14 years or older who were admitted to one of eight different hospitals located throughout the U.S. with acetaminophen exposures during a five and a half year span, encompassing from 1 January 2008 to 30 June 2013. Those patients who would be treated with the revised nomogram, but not the current nomogram were included. The cost of such treatment was extrapolated to a national level. RESULTS: 139 subjects were identified who would be treated with the revised nomogram, but not the current nomogram. Extrapolating these numbers nationally, an additional 4507 (95%CI 3641-8751) Americans would be treated annually for acetaminophen toxicity. The cost of lowering the treatment threshold is estimated to be $45 million (95%CI 36,400,000-87,500,000) annually. CONCLUSIONS: Adopting the revised treatment threshold in the U.S. would result in a significant cost, yet provide an unclear clinical benefit.