Generalized vitiligo is an autoimmune disorder of the skin in which autoimmune-mediated destruction of melanocytes leads to depigmented patches of skin and overlying hair. The 1858C>T (R620W) functional polymorphism of the PTPN22 gene, which encodes lymphoid protein tyrosine phosphatase (Lyp), has been associated with susceptibility to a number of autoimmune disorders, including generalized vitiligo. The aim of this study was to test genetic association of the PTPN22 1858C>T variant and generalized vitiligo in a Romanian case-control cohort. We observed significant association of generalized vitiligo with the 1858T risk allele of PTPN22 [P = 0.0138; OR = 2.92 (1.21-7.03)], with significantly different distribution of PTPN22 1858C>T genotypes in cases versus controls [P = 0.036; OR = 2.69 (1.07-6.80)]. Our results provide evidence that the PTPN22 1858T allele contributes to risk of generalized vitiligo in European Caucasian populations, and underscores the importance of a genetically mediated autoimmune mechanism in the pathogenesis of vitiligo.