Immature rat facial motoneurons are very sensitive to injury with nearly 80% dying during the first week after axotomy. This motoneuron death is apoptotic, similar to that induced in neurons after tropic factor withdrawal. The diphenylpiperazines, flunarizine and cinnarizine, protect dorsal root ganglion neurons from death after withdrawal of trophic support, i.e., nerve growth factor withdrawal, in vitro. Similarly, the monoamine oxidase inhibitor, deprenyl, promotes survival of facial motoneurons after axotomy. These pharmacological agents were assessed both alone and in combination for their ability to prevent death in non-nerve growth factor dependent CNS motoneurons after facial nerve axotomy in newborn rats. Long-term experiments were done with the diphenylpiperazines to evaluate potential enhancement of regeneration. Facial nerve transection resulted in 78% neuronal loss in the injured compared with the contralateral, uninjured nucleus. Systemic administration of diphenylpiperazines for 1 week after facial nerve transection doubled the number of surviving motoneurons from 23% to 47%. Similar results were obtained with deprenyl. Combinations of diphenylpiperazines and deprenyl provide a similar degree of neuronal protection l week after injury as that obtained by either agent alone. We assessed the ability of diphenylpiperazines to protect facial motoneurons from death over a prolonged period and enhance subsequent regeneration. Motor neuron counts in rats treated with diphenylpiperazines for 1 month after injury and assessed 2 months later demonstrated long-term enhancement of neuronal protection with an increase of 45% in the number of horseradish peroxidase-labelled motoneurons. The diphenylpiperazines group had ~80% more regenerated myelinated axons in the distal facial nerve than the control group. Thus, diphenylpiperazine treatment during the first month after injury provides long-term protection of non-nerve growth factor dependent CNS motoneurons with subsequent potentiation of long-term facial nerve regeneration.