Despite the advanced therapy with statins, antithrombotics and antihypertensive agents, the medical treatment of coronary artery disease is less than optimal. Therefore, additional therapeutic anti-atherosclerotic options are desirable. This VH-IVUS study (intravascular ultrasonography with virtual histology) was performed to assess the potential anti-atherogenic effect of the PPARγ agonist pioglitazone in non-diabetic patients. A total of 86 non-culprit atherosclerotic lesions in 54 patients with acute coronary syndrome were observed in a 9-month prospective, double-blind, and placebo-controlled IVUS study. Patients were randomized to receive either 30 mg pioglitazone (Pio) or placebo (Plac). As primary efficacy parameter, the change of relative plaque content of necrotic core was determined by serial VH-IVUS analyses. Main secondary endpoint was the change of total plaque volume. In contrast to placebo, in the pioglitazone-treated group, the relative plaque content of necrotic core decreased significantly (Pio −1.3 ± 6.9 % vs. Plac +2.6 ± 6.5 %, p < 0.01). In comparison to the placebo group, the plaques in pioglitazone-treated patients showed significantly greater reduction of the total plaque volume (Pio −16.1 ± 26.4 mm³ vs. Plac −1.8 ± 30.9 mm³, p = 0.02). Treatment with a PPARγ agonist in non-diabetic patients results in a coronary artery plaque stabilization on top of usual medical care.