Background: Recent studies highlight the beneficial effect of pioglitazone in reducing major adverse cardiovascular events (MACEs) in type 2 diabetic patients. We prospectively investigated the effects of pioglitazone in reducing MACEs after zotarolimus-eluting stent (ZES) implantation in type 2 diabetic patients during the 3-year follow-up. Methods: Type 2 diabetic patients with coronary artery diseases were randomly assigned to pioglitazone (n=91) or placebo (n=114) after ZES implantation. Baseline and 8-month coronary intravascular ultrasound (IVUS) were compared for neointimal growth. Primary endpoint was to compare MACEs such as non-fatal myocardial infarction, death, stroke, and target lesion revascularization (TLR) between the 2 groups during the 3-year follow-up. Secondary endpoints were to compare rates of new-onset heart failure, fracture, and non-TLR target vessel revascularization (TVR) between the 2 groups. Results: MACEs were significantly higher in the placebo group than the pioglitazone group during the follow-up [hazard ratio 2.326 (95% CI 1.167-4.638), p=0.016] (Figure 1). Rates of non-fatal myocardial infarction [odds ratio (OR) 1.011 (95% CI 0.989-1.033)], death [OR 0.974 (95% CI 0.945-1.004)], and stroke [OR 2.537 (95% CI 0.227-28.456)] showed no significant differences between the 2 groups; however, TLR [OR 0.322 (95% CI 0.144-0.721)] was significantly lower in the pioglitazone group than the placebo group. Rates of new-onset heart failure [OR 2.222 (95% CI 0.776-6.365)], fracture [OR 1.636 (95% CI 0.618-4.331)] and non-TLR TVR [OR 1.261 (95% CI 0.248-6.403)] revealed no significant differences between the 2 groups. Significantly lower neointima volume was detected in the pioglitazone group compared with the placebo group at 8 months (1.3짹0.7mm3/mm vs. 2.5짹1.4 mm3/mm, P<0.001). Conclusions: Rates of MACEs were significantly lower in the pioglitazone group when compared with the placebo group, mainly due to the lower rate of TLR during the 3-year follow-up.