Homocysteine (Hcy) is a metabolite of the essential amino acid methionine. Hyperhomocysteinemia is associated with vascular disease, particularly carotid stenosis. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma , attenuates balloon catheter-induced carotid intimal hyperplasia in type 2 diabetic rats. We studied 4 groups (n = 7 per group) of adult female Sprague-Dawley rats fed (a) powdered laboratory chow (control), (b) control diet with rosiglitazone (3.0 mg/kg/d), (c) diet containing 1.0% l -methionine, and (d) diet containing methionine and rosiglitazone. After 1 week on high methionine diet, the rats were administered an aqueous preparation of rosiglitazone by oral gavage. One week after initiation of rosiglitazone, balloon catheter injury of the carotid artery was carried out using established methods, and the animals continued on their respective dietary and drug regimens for another 21 days. At the end of the experimental period, blood samples were collected, and carotid arteries and liver were harvested. Serum Hcy increased significantly on methionine diet compared with controls (28.9 +/- 3.2 vs 6.3 +/- 0.04 micromol/L). Development of intimal hyperplasia was 4-fold higher in methionine-fed rats; this augmentation was significantly reduced ( P < .018) in rosiglitazone-treated animals. Rosiglitazone treatment significantly ( P < .001) suppressed Hcy levels and increased the activity of the Hcy metabolizing enzyme, cystathionine-beta-synthase in the liver samples. Hcy (100 micromol/L) produced a 3-fold increase in proliferation of rat aortic vascular smooth muscle cells; this augmentation was inhibited by incorporating rosiglitazone (10 micromol/L). After balloon catheter injury to the carotid artery of animals on a high methionine diet, there was an increase in the rate of development of intimal hyperplasia consistent with the known effects of Hcy. It is demonstrated for the first time that the peroxisome proliferator-activated receptor gamma agonist rosiglitazone can attenuate the Hcy-stimulated increase in the rate of development of intimal hyperplasia indirectly by increasing the rate of catabolism of Hcy by cystathionine-beta-synthase and directly by inhibiting vascular smooth muscle cell proliferation. These findings may have important implications for the prevention of cardiovascular disease and events in patients with hyperhomocysteinemia (HHcy).