Oxidative stress may be induced by increasing the generation of reactive oxygen species (ROS) and other free radicals. The generation of ROS is known to be associated with a decrease in antioxidant levels. In the present study, the role of oxidative stress was assessed in the pathogenesis of generalized vitiligo. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH) levels in erythrocytes and serum malondialdehyde (MDA) and nitric oxide (NO) levels were investigated in 24 patients with generalized vitiligo and 20 healthy controls. Our results indicated that significantly increased levels of erythrocyte SOD, serum MDA, and NO were associated with a marked reduction of erythrocyte GSH-Px and GSH activities in patients with generalized vitiligo (p < 0.05). Our observations suggest that the presence of an imbalance in the oxidant-antioxidant system might play a role in the pathogenesis of vitiligo. Our results further support the concept that free radical-mediated damage may be the initial pathogenic event in melanocyte degeneration in generalized vitiligo.