Semaphorin III has been described to function as a guidance molecule directing growing axons to their target. However, its effect on the neuron cell body has not been characterized. Semaphorin III has a highly dynamic expression pattern, which generally corroborates a chemorepellent guidance function, but also suggests additional functions, different from axon guidance. A number of studies show that some sensory neurons are eliminated, while their axons are still pathfinding. In this study we have investigated whether Semaphorin III also influences the survival of sensory neurons. We here present evidence that Semaphorin III can function in vitro as selective death factor for NGF-dependent sensory neurons. Semaphorin III induces a type of cell death that is characterized by slow onset, cell body shrinking, nuclear condensation, and TUNEL-positive staining of dying neurons. These are all hallmarks of neuronal apoptosis. We also show evidence that neurons can modulate the response to Semaphorin III. The novel function described here may also be relevant in vivo, contributing to active elimination of neurons during development or after injury.