The uncoupling protein (UCP) family has been suggested as a possible determinant affecting obesity risk given their function in the regulation of energy metabolism. In an effort to elucidate the effects of UCP family polymorphisms on obesity phenotypes, we genotyped 10 polymorphisms in UCP2 and UCP3 among overweight female subjects (n = 458), and genetic effects on BMI and changes after a very low calorie diet (VLCD) were examined. Analyses of VLCD-induced changes among the subjects who had finished one month-weight control program (n = 301) revealed that several polymorphisms in UCP2-3 gene cluster showed associations with changes of BMI and fat mass, however not of protein mass. One of the major haplotypes of UCP2-3 gene cluster, ht1 (GGCdelCGTACC), and UCP2-866G > A showed significant associations with VLCD-induced fat reduction (P = 0.002 and 0.004; P-corr = 0.03 and 0.01, respectively), and these results suggested that UCP2-3 polymorphisms were important genetic factor for the VLCD-induced reduction of body fat mass. (c) 2007 Elsevier Inc. All rights reserved.