BACKGROUND: The association between lipid levels and stroke rates is less than lipid levels and coronary heart disease (CHD). OBJECTIVE: To assess if there are geographic, racial, and ethnic differences in total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels with incident stroke. METHODS: From the REasons for Geographic And Racial Differences in Stroke (REGARDS) study we evaluated baseline levels of LDL-C, HCL-C, TC, Non-HDL-C (Total-HDL-C) and triglycerides in participants free of prevalent stroke at baseline. Cox Proportional-Hazard models were the main analytical tool used to examine the association between incident stroke and lipids. For each adjusted lipid measure (LDL-C, HDL-C, triglycerides, TC, and non-HDL-C) we calculated a series of incremental models. RESULTS: The analysis cohort was 23,867 participants with a mean follow-up time of 7.5±2.9years, and 1031 centrally adjudicated strokes (874 ischemic and 77 hemorrhagic strokes). HDL-C baseline level was associated with an overall unadjusted 13% risk reduction (HR 0.87, 95% confidence interval [CI]: 0.81-0.93; p<0.05; 14% for ischemic and 16% for hemorrhagic strokes), and TC with an 8% (HR 0.92, 95%CI: 0.87-0.99; p<0.05) risk reduction of all strokes. When the results were fully adjusted a significant association was observed only for LDL-C and non-HDL-C and ischemic stroke. There were no significant differences in these associations when adjusted for age, race, age∗race, gender, education, region, or income. CONCLUSION: In a disease free population, LDL-C and non-HDL-C baseline levels are significantly associated with the risk of ischemic stroke.