Insulin resistance may enhance the neointima formation via increased oxidative stress. However, clinical trials investigating the benefit of antioxidant therapy with alpha-tocopherol showed negative results. Recent studies showed that chemical characteristics of gamma-tocopherol are distinct from those of alpha-tocopherol. We hypothesized that gamma-tocopherol is superior to alpha-tocopherol in preventing the neointima growth after arterial injury in insulin resistance. Male rats were fed with standard chow or a high fructose diet for induction of insulin resistance. Thereafter, the left carotid artery was injured with a balloon catheter. After 2 weeks, the carotid arteries were harvested and histomorphometrically analyzed. The neointima-media ratio of the injured artery was significantly greater in insulin resistance group (n=8, 1.33+/-0.12) than in normal group (n=10, 0.76+/-0.11, p<0.01). gamma-Tocopherol (100 mg/kg/day) reduced the ratio (n=5, 0.55+/-0.21, p<0.01 vs. insulin resistance group), while alpha-tocopherol was without effect (n=7, 1.08+/-0.14). The quantification of plasma phosphatidylcholine hydroperoxide, an indicator of systemic oxidative stress, and dihydroethidium fluorescence staining of the carotid artery, an indicator of the local superoxide production, showed that oxidative stress in the systemic circulation and local arterial tissue was increased in insulin resistance. Both tocopherols decreased plasma phosphatidylcholine hydroperoxide, but failed to suppress the superoxide production in the carotid arteries. Increased 3-nitrotyrosine in neointima by insulin resistance was greatly reduced only by gamma-tocopherol. In conclusion, gamma-tocopherol, but not alpha-tocopherol, reduces the neointima proliferation in insulin resistance, independently of its effects on superoxide production. The beneficial effect may be related with its inhibitory effects on nitrosative stress.