FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of non-diabetic humans with varying obesity and insulin sensitivity. There was no relation between BMI and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled IV glucose tolerance test (r=-0.78, P<0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI, but who were discordant for S_I. When compared to the insulin sensitive subjects, the insulin resistant subjects had 3-fold higher levels of adipose FOXC2 mRNA (p=0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin resistant and insulin sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF, IL6, leptin, adiponectin, or non-esterified fatty acids. Thus, adipose FOXC2 is more highly expressed in insulin resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.