BACKGROUND: Early-onset severe toxicity following the administration of 5-fluorouracil (5-FU) or capecitabine occurs in approximately 10-30% of patients receiving fluoropyrimidine therapy in the USA and is fatal to at least 0.5% of patients treated. Supportive care measures used to manage symptoms of toxicity are associated with extended hospital length of stay, high cost of care, and poor survival. Uridine triacetate is indicated as an emergency treatment for patients who exhibit early-onset, severe or life-threatening toxicity, and has been shown to significantly improve clinical outcomes. Despite its life-saving capability to reverse early-onset severe toxicity, uridine triacetate may be underutilized. PURPOSE: This study aims to evaluate the economic impact of uridine triacetate as a rescue therapy for adult patients from the US hospital payer perspective for early-onset severe toxicity, who are expected to die without treatment. METHODS: A decision tree model was developed to compare inpatient survival, hospital length of stay, and inpatient healthcare resource utilization for patients treated with and without uridine triacetate. Costs associated with hospitalization, including supportive care measures and monitoring were evaluated, considering medications and procedures commonly used to manage various severe toxicities experienced (e.g., gastrointestinal, hematological, etc.). The model compared the hypothetical current practice, in which approximately half of patients expected to die from early-onset severe toxicity receive uridine triacetate in addition to supportive care, with the proposed future practice in which all eligible patients receive uridine triacetate during their hospital stay. Hypothetical practical scenarios for US institutions were also considered. RESULTS: For each adult patient hospitalized for early-onset severe or life-threatening toxicity who would be expected to die without treatment, adoption of uridine triacetate as a rescue treatment was associated with clinical benefits, including increased inpatient survival (48.5%) and a 7.3-day reduction in total hospital length of stay per patient. Treatment of each additional patient with uridine triacetate was associated with an incremental cost of US5,247 per patient. Seventy percent of the drug cost was offset by reduction in inpatient healthcare resources utilization. This cost offset is likely underestimated as it does not include additional savings from potential reimbursements associated with changes in hospital length of stay, readmissions and discounting. Hypothetical scenarios demonstrated that model outputs were most sensitive to changes in length of stay and hospitalization costs. CONCLUSION: Optimal treatment with uridine triacetate for all hospitalized patients in the USA expected to die from early-onset severe toxicity has the potential to improve inpatient survival at a minimal inpatient budget increase. The majority of the drug cost is offset by a reduction in the length of hospital stay and associated costs.