Obesity is a major risk factor for type II diabetes, hypertension, cardiovascular disease and certain forms of cancers. Obesity is a complex, multifactorial disorder, influenced by a network of genes, as well as diet, age, ethnicity, gender and exercise. Single nucleotide polymorphisms (SNPs) genotyped in six candidate genes for lipolysis and thermogenesis in human adipose tissue were used to identify and estimate epistatic quantitative trait loci (QTL) predisposing to human obesity based on linkage disequilibrium analysis for 105 black women and 538 white women drawn from the Womens Ischemia Syndrome Evaluation (WISE) study. A few pairs of epistatic QTL were found to affect different aspects of human obesity, including body weight, body mass index, waist and hip circumstances and their ratio, based on association studies of SNPs from different candidate genes. For example, two QTL associated with the β1-adrenergic receptor and Gs protein alpha subunit, respectively, trigger significant additive x additive, additive x dominant, dominant x additive and dominant x dominant epistatic effects on body weight in the black population. It appeared that more obesity QTL interactions occur in black than white populations, supporting the view that obesity genes may originate from Africa. Results from this study provide fundamental information about the genetic architecture of human obesity and the evolutionary mechanisms of population differentiation.