Plasma leptin has been suggested to be involved in the proatherogenic process by increasing oxidative stress. We investigated the relationships between leptin and insulin resistance, oxidative stress and furthermore, determined the role for leptin in in vivo lipid peroxidation of hypercholesterolemic patients. Seventy-six nondiabetic, hypercholesterolemic patients (mean age 59 yrs, 25 males and 51 females, LDL-cholesterol>=130mg/dL at screening) participated in the present study. Blood lipid profiles and HOMA-IR derived from fasting glucose and insulin concentrations were determined. Urine 8-epi-prostaglandin F2alpha excretion and blood leptin were analyzed using ELISA. The total subjects were classified into three groups according to the values of HOMA-IR as a measure of insulin resistance. Independent t-test was used to test the differences in continuous variables between the highest HOMA-IR group (n=25) and the lowest HOMA-IR group (n=25). Age, gender ratio, proportion of smokers, menopausal status, the existence of hypertension and current medication did not differ between the two groups. The highest HOMA-IR group had significantly higher body mass index (p<0.05) and triglyceride levels (p<0.05) than the lowest HOMA-IR gorup. Significantly higher levels of serum leptin (p<0.001) were observed in the highest tertile of HOMA-IR group. Furthermore, the highest tertile of HOMA-IR group had significantly higher urinary 8-epi-PGF2 alpha excretion (p=0.017) than the lowest HOMA-IR group. Stepwise multiple linear regression analysis was performed. The results showed that leptin was associated with the urinary 8-epi-PGF2 alpha excretion. These effects remained statistically significant after adjusting age, gender, body mass index, blood lipids and HOMA-IR as a measure of insulin resistance. To conclude, insulin resistant state of hypercholesterolemic patients is associated with the increased leptin levels. Furthermore, serum leptin is independent factor to determine urinary 8-epi-prostaglandin F2alpha excretion in hypercholesterolemic patients. Our study provides the understanding of the mechanisms linking adipocytokines, insulin resistance, atherosclerotic process and cardiovascular disease.