Peripheral nerve transection results in the rapid death by apoptosis of neonatal but not adult sensory and motor neurons. We show that this is due to induction and phosphorylation in all adult axotomized neurons of the small heat shock protein Hsp27 and the failure of such induction in most neonatal neurons. In vivo delivery of human Hsp27 but not a nonphosphorylatable mutant prevents neonatal rat motor neurons from nerve injury-induced death, while knockdown in vitro and in vivo of Hsp27 in adult injured sensory neurons results in apoptosis. Hsp27's neuroprotective action is downstream of cytochrome c release from mitochondria and upstream of caspase-3 activation. Transcriptional and posttranslational regulation of Hsp27 is necessary for sensory and motor neuron survival following peripheral nerve injury.