Increased expression of the cytokine interferon (IFN)-γ plays a pivotal role in vitiligo-induced depigmentation. However, the major source of IFN-γ in vitiligo patients and the mechanisms underlying melanocyte destruction are unknown. In this study, a large number of skin infiltrating IFN-γ+ cells and CD8+ T cells were detected in progressive vitiligo. Among the peripheral blood mononuclear cells (PBMCs) of vitiligo patients, CD8+ cytotoxic T lymphocytes (CTLs) that express IFN-γ exhibited significant expansion, which suggests that activated CTLs are the main source of increased IFN-γ in progressive vitiligo. An in vitro analysis demonstrated that IFN-γ inhibits melanogenesis in primary cultured human melanocytes by altering melanogenic enzyme mRNA expression and, more importantly, that IFN-γ directly induces melanocyte apoptosis. Our data indicate that vitiligo pathophysiology may be linked to globally activated CD8+ CTL subpopulations, which produce increased IFN-γ and induce melanocyte dysfunction and apoptosis.