For patients with profound hearing loss, cochlear implants have become the treatment of choice. These devices provide auditory information through direct electrical stimulation of the auditory nerve. Prosthesis function depends on survival and electrical excitability of the cochlear neurons. Degeneration of the auditory nerve occurs after lesions of its peripheral target field (organ of Corti), specifically, including loss of inner hair cells (IHCs). There is now evidence that local treatment of the cochlea with neurotrophins may enhance survival of auditory neurons after aminoglycoside-induced deafness. Glial cell line-derived neurotrophic factor (GDNF) has recently been shown to be an important survival factor in other regions of the nervous system. By in situ hybridization, we now show that IHCs of the neonatal and mature rat cochlea synthesize GDNF and that GDNF-receptor alpha, but not c-Ret, is expressed in the rat spiral ganglion. We also show that GDNF is a potent survival-promoting factor for rat cochlear neurons in vitro. Finally, we examined GDNF efficacy to enhance cochlear-nerve survival after IHC lesions in vivo. We found that chronic intracochlear infusion of GDNF greatly enhances survival of guinea pig cochlear neurons after noise-induced IHC lesions. Our results demonstrate that GDNF is likely to be an endogeneous survival factor in the normal mammalian cochlea and it could have application as a pharmacological treatment to prevent secondary auditory nerve degeneration following organ of Corti damage.