OBJECTIVE To describe the clinical presentation and successful treatment of a dog that ingested a lethal dose (approximately 330 mg/kg) of 5-fluorouracil (5-FU). METHODS A 1-year-old male intact German Shepherd dog was presented to the Emergency Service of the Ohio State University Veterinary Medical Center after ingesting 10 g of 5% 5-FU cream. The dog rapidly developed refractory seizures and was managed by inducing heavy sedation with phenobarbital, benzodiazepines, ketamine, and propofol, necessitating 48 hours of mechanical ventilation. Seizure activity continued despite these treatments until IV administration of levetiracetam. The dog was discharged from the hospital 6 days after admission and remains neurologically normal currently, with no further seizure activity after 9 months. This report documents the first successful treatment of a dog that ingested > 43 mg/kg of 5-FU. In this case, the use of rapid decontamination, heavy sedation with anticonvulsant medications including levetiracetam to control seizures, and mechanical ventilation may have contributed to a positive outcome.