Cytologic evidence of herpes viral infection within cells from body cavity effusions is extremely uncommon. The authors report the case of a 57-year-old woman who was treated with chemotherapy and irradiation for malignant lymphoma and subsequently developed disseminated varicella-zoster infection with pleural involvement. Cytologic examination of pleural fluid revealed cytopathic changes caused by the varicella-zoster virus, which were confirmed by electron microscopy and viral culture of the effusion. The cytologic and ultrastructural features of the virus-infected cells are described, and the pathogenesis of the effusion and sequence of events in varicella-zoster virus-cell interaction are discussed.