Objective: Biglycan, a non-fibrillar component of extracellular matrix (ECM), is released from the matrix by the action of proteolytic enzymes upon tissue stress or injury. The soluble form of biglycan can bind to toll-like receptor (TLR) 2/4 on macrophages, resulting in secretion of proinflammatory cytokines and chemokines. We hypothesized that overexpression of biglycan might participate in inflammatory reactions in adipose tissues of obese humans and thereby, contribute to the pathogenesis of obesity-related disorders such as insulin resistance. Methods: We recruited 21 non-diabetic obese women, 11 type 2 diabetic obese women, and 59 normal-weight women. Metabolic parameters, abdominal fat distribution, and biglycan mRNA expression in abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured. In addition, the induction of biglycan was tested by co-culturing human preadipocytes or differentiated adipocytes with THP-1 macrophages. Results: Regardless of diabetes status, obese patients demonstrated significantly higher levels of biglycan mRNA in both VAT and SAT. Biglycan mRNA was expressed in adipocytes as well as non-adipocytes, but predominantly in the latter. Biglycan mRNA in fat depots was significantly and positively correlated with insulin resistance-related metabolic parameters. In both fat depots, biglycan mRNA was independently related with CD68 mRNA. In addition, co-culture with macrophage significantly elevated biglycan mRNA in human preadipocytes and differentiated adipocytes. Conclusion: Our data provide clear evidence that biglycan plays a key role in initiating and amplifying inflammatory responses in expanding adipose tissues during the development of obesity in humans and suggest that enhanced biglycan expression in adipose tissues may contribute to the pathogenesis of obesity-related disorders such as insulin resistance.