OBJECT: Vagus nerve stimulation is known to decrease the frequency, duration, and intensity of some types of intracranial seizures in both humans and animals. Although many theories abound concerning the mechanism for this action, the true cause remains speculative. To potentially elucidate a pathway in which vagus nerve stimulation aborts seizure activity, seizures were initiated not in the cerebral cortex but in the spinal cord and then vagus nerve stimulation was performed. METHODS: Ten pigs were anesthetized and placed in the lateral position, and a small laminectomy was performed in the lumbar region. Topical penicillin, a known epileptogenic drug to the cerebral cortex and spinal cord, was applied to the dorsal surface of the exposed cord. With the exception of two animals that were used as controls, once seizure activity was discernible via motor convulsion or increased electrical activity the left vagus nerve, which had been previously isolated in the neck, was stimulated. Following multiple stimulations of the vagus nerve and with seizure activity confirmed, the cord was transected in the midthoracic region and vagus nerve stimulation was performed. Vagus nerve stimulation resulted in cessation of spinal cord seizure activity in all (87.5%) but one experimented animal. Transection of the spinal cord superior to the site of seizure induction resulted in the ineffectiveness of vagus nerve stimulation to cause cessation of seizure activity in all study animals. CONCLUSIONS: The effects of vagus nerve stimulation on induced spinal cord seizures involve descending spinal pathways. The authors believe that this experiment is the first to demonstrate that spinal cord neuronal hyperactivity can be suppressed by stimulation of a cranial nerve. These data may aid in the development of alternative mechanisms for electrical stimulation in patients with medically intractable seizures. Further studies are now necessary to isolate which specific tracts, nuclei, and neurotransmitters are involved in this process.