This study examined differences in adipose tissue biology between insulin-sensitive (IS) and insulin-resistant (IR) obese individuals matched for body mass index (BMI), age and sex with paired samples from abdominal subcutaneous and intra-abdominal omental adipose tissue. The study sample included 60 morbidly obese men and women with a mean BMI of 45±1.3 kg/m2 who were divided to IS or IR on the basis of glucose infusion rate during euglycemic-hyperinsulinemic clamps. Results showed that, independently of BMI and total body fat mass, the IR obesity group was characterized by increased intra-abdominal fat area, increased macrophage infiltration into omental adipose tissue and enlarged adipocyte size in both omental and subcutaneous fat depots. Moreover, they were also represented with dysregulation of circulating adipokines and cytokines such as decreased adiponectin and increased progranulin, chemerin, retinol-binding protein-4 and fetuin-A serum concentrations. Among the parameters of adipose tissue function, macrophage infiltration in omental adipose tissue and circulating adiponectin were the two best predictors of insulin sensitivity (r2>=0.98, p<0.0001). In addition, prediction of insulin sensitivity was similar whether intra-abdominal fat area or estimated hepatic steatosis alone was included in the model. These results suggest that adipose tissue inflammation may be the link between obesity and insulin resistance, therefore supporting the need to consider adipose tissue dysfunction and not only caloric imbalance to predict the risk associated with obesity.