Introduction: The association of DHEAS with coronary risk has been extensively studied, but little information is available on stroke risk. DHEAS levels are lower with stroke risk factors such as atrial fibrillation, arterial stiffness and atherosclerosis, but only one paper evaluated stroke risk and showed an inverse association of DHEAS and stroke risk in female nurses. Hypothesis: We assessed the hypothesis that lower DHEAS level is associated with increased ischemic stroke risk. Methods: REGARDS enrolled 30,239 US participants aged 45 and older in 2003-07 (41% black, 59% white, 55% living in the southeastern stroke belt). Baseline serum DHEAS was measured in 1,578 participants; 963 in a cohort random sample and 544 with first-time ischemic stroke during 5.4 years of follow up. Cox proportional hazard models with weights to account for the case cohort design were used to calculate hazard ratios (HR) of stroke by quartiles of DHEAS levels. Results: DHEAS was significantly lower with older age, white race, female sex, and history of heart disease. DHEAS in the first compared to the fourth quartile was associated with increased risk of stroke (HR 1.7, CI: 1.2-2.4), although this association was not present after adjusting for age (or other stroke risk factors: HR 1.0, CI: 0.7-1.6). These findings were similar in men and women. Stratifying on age, as shown in the table, in those <65 at baseline, lower DHEAS was associated with increased stroke after adjustment for sex, race, and Framingham stroke risk factors (HR 3.1, CI: 1.3-7.6), but there was no association in those >65 years (HR 0.8, CI: 0.5-1.4). Conclusion: There was no overall association of lower DHEAS and stroke risk in this bi-racial cohort of men and women from across the US, although a possible difference by age was observed. More research is needed to determine association of DHEAS with stroke risk.