Vitiligo is an acquired hypomelanotic skin disorder resulting from the loss of functional melanocytes. The COMT-158 polymorphism can reduce COMT enzyme activity and may thus lead to the overproduction of toxic radicals in the melanocyte microenvironment. To determine whether this polymorphism in the COMT gene is associated with an increased risk of vitiligo in Chinese populations, we used a polymerase chain reaction sequence-specific primer (PCR-SSP) technique to determine the frequency of the polymorphism COMT-158 G > A in 749 vitiligo patients and 763 healthy controls. We found that compared to the COMT-158 GG genotype, the COMT-158 GA genotype (adjusted odds ratio [OR], 1.39; 95% confidence interval [CI], 1.13-1.72) and the combined GA + AA genotype (adjusted OR, 1.41; 95% CI, 1.15-1.74) were associated with an increased risk of generalized vitiligo. The association was more pronounced in patients with early-onset vitiligo (adjusted OR, 1.95; 95% CI, 1.45-2.60), those with a family history of vitiligo (adjusted OR, 3.84; 95% CI, 2.47-5.96), and female patients (adjusted OR, 1.74; 95% CI, 1.29-2.36). When we further clinically stratified the vitiligo patients according to their disease types, we found that the combined GA + AA genotype was associated with vitiligo vulgaris (adjusted OR, 1.31; 95% CI, 1.02-1.68), focal vitiligo (adjusted OR, 1.62; 95% CI, 1.17-2.25), and universal vitiligo (adjusted OR, 1.50; 95% CI, 0.98-2.30), but not with acrofacial vitiligo (adjusted OR, 1.53; 95% CI, 0.86-2.73) or segmental vitiligo (adjusted OR, 1.35; 95% CI, 0.72-2.51). In conclusion, this COMT gene polymorphism may have contributed to the etiology of vitiligo in our Chinese population. Larger population-based studies are required to verify our findings.