Uncoupling protein (UCP) is a mitochondrial inner-membrane protein that is involved in energy homeostasis. In human tissues, UCP2 is widely expressed, acts as an uncoupling agent for oxidative phosphorylation, and is involved in the regulation of metabolism and ATP production. The association between UCP2 45bp Ins/Del gene polymorphism and the risk of overweight and obesity remains controversial and requires further evaluation. A meta-analysis of 12,224 subjects in 20 articles from PubMed, Embase, and China National Knowledge Infrastructure was performed to assess the association of UCP2 45bp Ins/Del gene polymorphism with the risk of overweight and obesity. The results of the meta-analysis showed that the UCP2 45bp Ins/Del gene polymorphism was significantly associated with genetic susceptibility to overweight and obesity only in the recessive model (odds ratio [OR]=1.24, 95% confidence interval [CI]=1.07-1.43, P=0.004), while the rest of the models did not show an association (P﹥0.05). However, the subgroup analysis of ethnicity showed that, in Asian populations, UCP2 45bp Ins/Del gene polymorphism was associated with genetic susceptibility to overweight and obesity in the allelic (OR=1.18, 95%CI=1.02-1.36, P=0.027), dominant (OR=1.20, 95%CI=1.02-1.41, P=0.030), and heterozygote (OR=1.19, 95%CI=1.01-1.41, P=0.043) models, respectively. No significant associations were found in the Caucasian population (P﹥0.05), and there was significant heterogeneity between the studies. UCP2 45bp Ins/Del gene polymorphism, which is significantly associated with genetic susceptibility to overweight and obesity in Asian populations, is not significantly associated with genetic susceptibility to obesity in Caucasian populations.