Inflammation is involved in the pathophysiologic process of atherosclerosis, a frequent complication of type 2 diabetes. The purpose of our study was to investigate the effect of pioglitazone on systemic inflammatory markers and activation of circulating monocytes in type 2 diabetic patients through the dosage of IL-6. Twenty-four metformin-treated patients, in good glycemic control, were randomized to add pioglitazone for 8 weeks or to continue their previous treatment. Blood samples were collected before and at the end of the study to evaluate: serum levels of high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6 and leukocyte activation. IL-6 production of circulating monocytes after LPS stimulation was similar at baseline and showed a 54% reduction in pioglitazone-group at 8 weeks (9.1 pg/mL, range 0.0-24.3, P=0.04 vs. baseline) while, in controls, did not change at 8 weeks (16.9 pg/mL, range 1.5-58.8). Treatment with pioglitazone, associated with metformin, showed a reduction of IL-6 monocyte production after their in vitro activation with LPS.