Uncoupling protein 3 (UCP3) uncouples ATP production from mitochondrial respiration, thereby dissipating energy as heat and affecting the efficiency of energy metabolism. Genetic variations in the UCP3 gene have been conceived to affect body weight in the general population. In this study, using the quantitative transmission disequilibrium test (QTDT), we assessed linkage and association between the UCP3 gene and obesity phenotypes in a large sample of 1,873 subjects from 405 United States Caucasian nuclear families. Obesity phenotypes tested include body mass index (BMI), fat mass, percent fat mass (PFM), and lean mass, with the latter three measured by dual-energy X-ray absorptiometry. We first selected five single nucleotide polymorphisms (SNPs) and then analyzed three highly polymorphic ones, namely, -55 C/T (promoter), Tyr99Tyr (exon 3), and Tyr210Tyr (exon 5), in the total sample. Significant linkage disequilibria (0.392 <or= D' <or= 0.940, P < 0.0001) were observed between pairs of SNPs. In single-locus analyses, we found statistically significant association (P = 0.034) and linkage (P = 0.031) between -55 C/T and BMI. This polymorphism explains 2.29% of BMI variation, and subjects carrying the T allele had an average of 3.5% lower BMI than those without it (P = 0.003). In haplotype analyses, we also observed evidence of linkage (P = 0.002) and association (P = 0.035) with BMI. In summary, our results suggest that UCP3 gene polymorphisms may contribute to BMI variation in this Caucasian population.