REM sleep is the most antiepileptic state in the sleep-wake cycle for human generalized epilepsy, yet the neural mechanism is unknown. This study verified the antiepileptic properties of REM sleep in feline generalized epilepsy and also isolated the responsible factors. Conclusions are based on 20 cats evaluated for generalized EEG and motor seizure susceptibility before and after dissociation of specific REM sleep components. Bilateral electrolytic lesions of the medial-lateral pontine tegmentum created a syndrome of REM sleep without atonia. Systemic atropine created a syndrome of REM sleep without thalamocortical EEG desynchronization. Identical results were obtained in two seizure models, systemic penicillin epilepsy and electroconvulsive shock. (1) Normal REM sleep retarded the spread of EEG seizure discharges and had even more potent anticonvulsant effects. (2) Selective loss of 'sleep paralysis' (skeletal muscle atonia) during REM abolished REM sleep protection against myoclonus and convulsions without affecting generalized EEG paroxysms. (3) Conversely, selective loss of thalamocortical EEG desychronization abolished REM sleep protection against generalized EEG seizures without affecting clinical motor accompaniment. These results suggest that the descending brainstem pathways which mediate lower motor neuron inhibition also protect against generalized motor seizures during REM sleep. Protection against spread of EEG paroxysms is governed by a separate mechanism, presumably the ascending brainstem pathways mediating intense thalamocortical EEG desynchronization during REM sleep.