The uncoupling protein 3 (UCP3) is a mitochondrial membrane transporter mainly expressed in skeletal muscle that we have shown to be associated with obesity. We have analyzed UCP3 polymorphisms, Val102Ile, Tyr210Tyr, and a new microsatellite GAIVS6 located in the sixth intron, among 276 black and 503 white subjects from the HERITAGE Family Study. Linkage and association studies were undertaken with body composition variables measured in a sedentary state (baseline) and after 20 wk of endurance training (changes). Allele and genotype frequencies were found to be significantly different between whites and blacks. Suggestive linkages (0.009 < or = P < or = 0.033) with Tyr210Tyr were found in blacks and whites for baseline body mass index, fat mass, or leptin level and with GAIVS6 in whites for changes in fat mass and percent body fat. Associations were also found in whites between GAIVS6 and changes in the sum of eight skinfold thicknesses (P = 0.0006), with a borderline result for body mass index (P = 0.06). We concluded that UCP3 could be involved in body composition changes after regular exercise.