Varicella pneumonia is one of the most serious, potentially life-threatening complications of primary varicella-zoster virus (VZV) infection in adults and immunocompromised individuals. However, studies on the lung pathogenesis of VZV infection as well as development and testing of antivirals have long been hindered by limited access to clinical samples and a lack of suitable animal models. In this study, we report for the first time the use of human lung xenografts in SCID mice for investigating VZV infection. Human fetal lung tissues grafted under the kidney capsule of SCID mice rapidly grew and developed mature structures closely resembling normal human lung. Following infection, VZV replicated and spread efficiently in human lung xenografts, where the virus targeted both alveolar epithelial and mesenchymal cells, and resulted in formation of large viral lesions. VZV particles were readily detected in the nuclei and cytoplasm of infected lung cells by electron microscopy. Additionally, VZV infection resulted in a robust pro-inflammatory cytokine response in human lung xenografts. In conclusion, infecting human lung xenografts in SCID mice provides a useful, biological relevant tool for future mechanistic studies on VZV lung pathogenesis, and may potentially facilitate the evaluation of new antiviral therapies for VZV lung infection.