Body weight regulation is a complex phenotype also depending on the action of uncoupling proteins (UCPs) that mediate the "uncoupling" of respiration leading to the dissipation of energy as heat. This study investigated whether genetic variants in the genes encoding UCP-1 and UCP-3 are associated with different obesity-related phenotypes in 162 whites with a wide range of body mass index. All subjects were genotyped for the polymorphisms UCP-1 A-3826G, UCP-1 Ala64Thr, and UCP-3 C-55T using a PCR-based restriction method with appropriate enzymes. The frequencies of the UCP-1 3826G, UCP-1 64Thr, and UCP-3 55T alleles were 27.2%, 12.0%, and 22.8%, respectively. No significant associations were observed between polymorphism and body mass index or obesity. However, after adjustment for gender, age, body mass index, and diabetes mellitus the waist-to-hip ratio was significantly associated with UCP-1 Ala64Thr ( P=0.003) and UCP-3 C-55T ( P=0.02) but not with UCP-1 A-3826G. The higher waist-to-hip ratios associated with the UCP-1 64Thr and UCP-3 55T alleles were due to higher waist circumference in these allele carriers. In conclusion, central obesity in whites as reflected by an increased waist-to-hip ratio is associated with the UCP-1 Ala64Thr and UCP-3 C-55T polymorphisms. To what extent these genotypes contribute to the overall cardiovascular risk remains to be elucidated.