Objective-Recent studies highlight the beneficial effect of pioglitazone in attenuating neointimal growth after stent implantation. We investigated the mechanistic basis underlying anti-restenosis and anti-atherogenic effect of pioglitazone in type 2 diabetic patients undergoing zotarolimus-eluting-stent implantation. Methods and Results-Patients with coronary artery diseases were randomly assigned to pioglitazone (n=47) or placebo (n=47) after stent implantation. Pioglitazone significantly reduced neointimal hyperplasia within the stented lesion and attenuated total plaque burden in the in-segment regions of the stent, as assessed by intravascular ultrasonography at the 8-month follow-up. These changes were preceded by reduced circulating NK cells, diminished IL-6 and MCP-1, and downregulation of chemokine receptor 2 at 2 days following stent implantation and elevated IL-10 at 10 days after implantation. Furthermore, proliferation and migration of vascular smooth muscle cells were inhibited under the presence of pioglitazone-treated patient���s sera, demonstrating that anti-proliferative effects of pioglitazone occurred concurrently with its anti-inflammatory action. Conclusions-Our data present early cellular and immunologic changes by pioglitazone that might have been associated with anti-restenotic and anti-atherogenic effects in diabetic patients. Inhibition of pro-inflammatory responses while promoting anti-inflammatory circuits together with anti-proliferative action may in part account for anti-restenotic effect of pioglitazone via altering vascular remodeling processes in the early phase.