Infiltration of monocyte-derived macrophages into adipose tissue may contribute to tissue and systemic inflammation and insulin resistance. We hypothesized that pioglitazone could specifically reduce inflammatory response of adipocytes to factors released by monocytes/ macrophages. We show that macrophage-factors (M-factors) greatly increased the expression levels of pro-inflammatory adipokines, chemokines, and adhesion molecules in human subcutaneous and visceral adipose tissue (SAT and VAT) as well as in adipocytes (up to several hundred fold of control). Compared with SAT, VAT show enhanced basal and M-factor-induced inflammatory responses. M-factors also induced greater lipolysis in adipocytes as assessed by glycerol concentrations released from the cells (196±13 vs. 56±7 µM in control, P<0.05). Pretreatment of adipose tissue or adipocytes with pioglitazone reduced the above responses to M-factors (by 13-86%, P<0.05) and prevented M-factor-suppression of adiponectin expression. Furthermore, pioglitazone pre-treatment of both adipocytes and macrophages tended to further reduce inflammatory responses of adipocytes to M-factors and monocyte adhesion to M-factor-activated adipocytes. In support of these in vitro data, media conditioned by monocytes isolated from impaired glucose tolerant subjects who had received pioglitazone treatment (compared with placebo) induced lower concentrations of pro-inflammatory adipokines and glycerol (100±7 vs.150±15 µM, P<0.05) released from adipocytes. In summary, pioglitazone decreases inflammatory responses in adipose tissue/cells induced by monocytes/macrophages by acting on either or both cell types. These beneficial effects of pioglitazone may attenuate pro-inflammatory responses resulting from monocyte/macrophage infiltration into adipose tissue and suppress tissue inflammation resulting from the interaction between both cell types.