The uncoupling protein-1 (UCP1) gene is of major importance for regulation of body weight and lipid/lipoprotein metabolism. Our cross-sectional study has shown that subjects with the G/G genotype of the -3826 A/G polymorphism in the UCP-1 gene have higher levels of serum high-density lipoprotein cholesterol (HDL-C) than those with other genotypes. Low circulating HDL-C level has been regarded as a major atherosclerotic risk factor. We therefore investigated whether the -3826 A/G polymorphism affects the obesity- and lipid-related parameters during a low-calorie diet (LCD) intervention. In 32 obese women (49.9 +/- 8.4 years of age), anthropometric, physiological and biochemical characteristics were measured before and after a 2-month LCD treatment, which restricted each subject to the same energy intakes, such as 5,120 kJ/day. The -3826 A/G polymorphism was detected using a PCR-restriction fragment-length polymorphism method. There were 6 subjects with the A/A genotype, 15 with the A/G genotype and 11 with the G/G genotype. The LCD intervention decreased weight (P < 0.001) and serum HDL-C levels (P < 0.05) in all subjects. There was no difference in the levels of change in weight, nutrient intake, physiological measurements in energy expenditure, and fat oxidation between subjects with and without the G allele. In contrast, the degree of the reduction in the HDL-C levels was significantly smaller in subjects with the G allele than those without the G allele. These results suggest that the G allele at -3826 in the UCP1 gene may ameliorate the reduction in serum HDL-C levels in obese women during LCD.