Although polymorphism of the mitochondrial DNA 15497guanine/adenine (Mt15497G-->A) leads to the Gly251Ser amino acid replacement on human cytochrome b, it is unknown whether functional alteration of the mitochondrion is induced by the Gly251Ser replacement. To see if an association exists between the Mt15497G-->A polymorphism and obesity, we examined differences in body size, body composition, and regional body fat distribution between the two genotypes in middle-aged and elderly Japanese individuals (825 women and 906 men). The Mt15497 genotype was determined with an automated colorimetric allele-specific DNA probe assay system using the polymerase chain reaction (PCR) method. The Mt15497G-->A polymorphism was detected in 3.5% ( n=60) of all subjects: 2.8% ( n=23) among women and 4.1% ( n=37) among men. After adjusting for age and smoking, we found that body weight, body mass index, waist and hip circumferences, fat mass, fat-free mass, intra-abdominal fat and triglycerides were significantly greater in women with the A allele compared with the G allele ( p=0.001-0.025). For men, waist to hip ratio was significantly greater ( p=0.032), and waist circumference, intra-abdominal fat and triglycerides had a trend to be significantly greater ( p=0.062-0.087) in subjects with the A allele compared with the G allele. These data suggest that the Mt15497 polymorphism may be associated with obesity-related variables and lipid metabolism.