The pathogenesis of the loss of melanocytes in patients with vitiligo is complex and involves the concurrent actions of multiple mechanisms, including genetic, immune-mediated, intrinsic, oxidative, and environmental factors. Although melanocyte loss is ultimately driven by cytotoxic CD8+ cells, the distinctive role of each involved element and the priming causes responsible for triggering the sequence of events culminating in the autoimmune-mediated melanocyte disappearance are yet to be highlighted. Oxidative stress has been considered one of the pathogenetic mechanisms involved in melanocyte disappearance. We have previously demonstrated that melanocytes also fibroblast from pigmented skin of patients with vitiligo present an increased intracellular ROS level associated with a pre-senescent phenotype. More recently, we described in vitiligo keratinocytes a defect of the differentiation process. All the cell populations examined presented an alteration of glucose metabolism and mitochondrial morphology. To evaluate whether a metabolic alteration generated oxidative stress, we assessed the role of a PPARy activator, capable of improving glucose metabolism, in controlling the phenomenon. The PPARy activator improved glucose metabolism, decreased ROS generation, and modified the biological behavior in all the cell cultures tested. Our results indicate that a metabolic abnormality characterizes the skin cell of vitiligo patients, which could be the basis of the continuous intracellular oxidative stress and the increased sensitivity to external stress. Prospectively a “metabolic” approach to the disease could be evaluated