Brain-derived neurotrophic factor (BDNF) plays a critical role in the development of the central and peripheral nervous systems, and also in neuronal survival after injury. The actions of BDNF are mediated by its high-affinity receptors TrkB and p75NTR. Recent studies have shown that proneurotrophins bind p75NTR and sortilin with high affinity, and trigger apoptosis of neurons in vitro. As proneurotrophins are a dominant form of gene products in developing and adult animals, it is imperative to understand their physiological functions in animals. Here, we showed differential roles of proBDNF in injured and uninjured sensory neurons. proBDNF, p75NTR and sortilin are highly expressed in dorsal root ganglia (DRG) neurons. Recombinant proBDNF induced a dose-dependent death of PC12 cells and the death activity was completely abolished in the presence of antibodies against the prodomain of BDNF. The exogenous proBDNF enhanced the death of axotomized sensory neurons and the neutralizing antibodies to the prodomain or exogenous sortilin-extracellular domain-Fc fusion molecule reduced the death of axotomized sensory neurons. Interestingly, the treatment of neutralizing antibody in vivo increased the number of sensory neurons in the contralateral DRG. We conclude that proBDNF may induce the death of axotomized sensory neurons and suppress neuronal addition in the intact DRG in neonatal rats, and the suppression of endogenous proBDNF may protect neurons after neurotrauma.