Based on in vitro studies, it is hypothesized that neurotrophic factor deprivation following deafferentation elicits an oxidative state change in the deafferented neuron and the formation of free radicals that then signal cell death pathways. This pathway to cell death was tested in vivo by assessing the efficacy of antioxidants (AOs) to prevent degeneration of deafferented CNVIII spiral ganglion cells (SGCs) in deafened guinea pigs. Following destruction of sensory cells, guinea pigs were treated immediately with Trolox (a water soluble vitamin E analogue)+ascorbic acid (vitamin C) administered either locally, directly in the inner ear, or systemically. Electrical auditory brainstem response (EABR) thresholds were recorded to assess nerve function and showed a large increase following deafness. In treated animals EABR thresholds decreased and surviving SGCs were increased significantly compared to untreated animals. These results indicate that a change in oxidative state following deafferentation plays a role in nerve cell death and antioxidant therapy may rescue SGCs from deafferentation-induced degeneration.