A polymorphism in the promoter region of uncoupling protein 2 gene -866G/A has been associated with its expression levels in adipose tissue, the risk of obesity, and metabolic abnormalities. Our purpose was to examine the associations of -866G/A with body fat and the risk of metabolic syndrome in a random sample of 4018 Asians (1858 men and 2160 women) from three ethnic groups (Chinese, Malay, and Indian). The minor allele frequency of -866G/A polymorphism in South Asians was similar to that in whites. After adjustment for covariates including age, cigarette smoking, and physical activity, the -866A/A genotype was associated with higher waist-to-hip ratio as compared with the wild-type genotype in Chinese and Indian men (p = 0.018 and p = 0.046, respectively). Moreover, Indian men with -866A/A genotype had a significantly increased risk of metabolic syndrome as compared with those homozygous for the wild-type (odds ratio, 2.66; 95% confidence interval, 1.21 to 5.88; p = 0.015). Such a risk was mainly caused by the excess presence of hypertriglyceridemia and central obesity. Our findings indicate that the uncoupling protein 2 gene -866G/A polymorphism may increase the risks of central obesity and metabolic syndrome, with greater effects on Asian men.