We have previously demonstrated that neurotrophin-3 antiserum administration to rats during the first 2 postnatal weeks results in a massive reduction of neurons in the superior cervical ganglion. In the present study, an ultrastructural analysis was undertaken to elucidate the mechanism by which neurotrophin-3 deprivation causes neuronal death. Newborn and 4-week-old rats were injected with either neurotrophin-3 antiserum or normal rabbit serum or used without injection. Superior cervical ganglia from each animal were examined by routine electron microscopy. Most neurons in the ganglia from untreated rats had a large and round nucleus with one or two nucleoli. Chromatin within the nucleus was evenly distributed. A double- layer nuclear membrane could be distinguished and the cytoplasm contained abundant organelles. Treatment with neurotrophin-3 antiserum for 24 h in neonates resulted in chromatin clumping in the nucleus of many neurons. The nuclear membrane became rough and occasionally folded. In the cytoplasm, the Golgi apparatus was disrupted. Three days after treatment, these changes became more obvious. The chromatin in the nucleus was often aggregated and marginalized. Vacuolation was present in many membranous organelles throughout the cytoplasm. Although neurotrophin-3 antiserum given to 4-week- old rats had little effect on overall neuronal numbers (Tafreshi, Zhou, and Rush, unpublished), a few neurons, undergoing either apoptotic or cytolytic cell death, were identified 7 days later. Most affected neurons were located near small blood vessels or capillaries and were associated with numerous nonneuronal cells. The debris of degenerating neurons were surrounded by the processes of glia cells. These findings support the view that loss of endogenous neurotrophin-3 following neutralization with specific antibody leads to activation of apoptotic pathways within the affected neurons. However, the presence of neurons dying as a result of cytolysis suggests that other mechanisms may also be involved.