This study was conducted to compare the expression of genes regulating adipogenesis, lipogenesis, and inflammation in adipose tissue as well as lipotoxicity between African-American and Caucasian women. For that purpose, a total of 83 healthy and nondiabetic Caucasian and 34 African-American subjects were enrolled in this study. Analyses revealed that despite similar body mass index values, African-American women had decreased total body fat, but higher subcutaneous adipose tissue and lower intra-abdominal (visceral) adipose tissue when compared with Caucasian women. At the same level of insulin sensitivity, African-American women had higher acute insulin response to glucose (AIRg), decreased plasma adiponectin levels and intramyocellular lipid, but similar plasma tumour-necrosis factor-a and interleukin-6 levels when compared with Caucasian women. Moreover, African-American women also had a more favourable blood lipid profile. No differences in leptin and CD68 gene expression in subcutaneous adipose tissue of African Americans were found when compared to Caucasian women. The expression of a number of genes involved in adipogenesis and lipogenesis in subcutaneous adipose tissue and muscle were decreased in African Americans such as peroxisome proliferator-activated receptor-g, lipin-1β, AGPAT 2, SCD1, CD36 and ATGL. Regarding intramyocellular lipids, an index of lipotoxicity, it correlated strongly with insulin sensitivity, but only in Caucasians. Thus, these data suggest that there are significant ethnic differences in the mechanistic pathways leading to insulin resistance and type 2 diabetes.