Primary varicella-zoster virus (VZV) infection of humans may result in latent infection of sensory neurons in the peripheral nervous system. To examine the interaction of VZV with the sensory neuron we infected immunochemically defined human neurons with cell-associated VZV. Utilizing double-label immunofluorescence technology, a VZV-specific glycoprotein and a nonglycosylated phosphoprotein were detected in human fetus dorsal root ganglion (DRG) neurons, as defined by the presence of the neuron-specific enolase isoenzyme and the A2B5 ganglioside antigen, respectively. In addition to VZV antigen expression, progressive virus-induced cytopathic damage (neuronal enlargement and nuclear granulation of a fraction of the neuron population) was evident. As determined by transmission electron microscopy, VZV-infected human fetus DRG neurons contained empty and complete nucleocapsids with numerous pleomorphic virus particles in the cytoplasm, often in association with vacuoles. Although virus-specific antigen expression, particle synthesis, and cytopathic effects were observed in the human neuron population, neurons were less susceptible to VZV-induced cytopathic damage than supporting nonneuronal cells, suggesting neuronal modulation of VZV infection in vitro. This system provides the first model to examine the neuron- and virus-specific gene(s) and gene product(s) pertinent to the interaction of VZV with the human neuron.