Although the original homocysteine hypothesis for atherothrombotic disease is falling out of favor, prior studies did not comprehensively adjust for confounders or explore specific subgroups of patients who may benefit from serum homocysteine-lowering. We aimed to determine (1) if elevated total homocysteine (tHcy) affects odds of prevalent stroke after adjusting for a broad array of pertinent covariates and (2) whether particular vascular risk factors amplify the effect of high homocysteine on prevalent stroke. The independent and interactive effects of elevated tHcy (≥10 μmol/L) on likelihood of prevalent stroke was assessed in the National Health and Nutrition Examination Survey, a nationally representative cross-sectional sample of the US population conducted from 1999 to 2004 (n=12,683). After adjusting for 17 covariates, those with elevated tHcy were more likely to have prevalent stroke vs. those without elevated tHcy (OR 1.52, 95% CI 1.01-2.29; p=0.045). Individuals with a combination of elevated tHcy and hypertension were substantially more likely to have prevalent stroke compared to individuals without either condition (OR 12.02, 95% CI 6.36-22.73 for men and OR 17.34, 95% CI 10.49-28.64 for women). The association of tHcy with prevalent stroke was strongest in younger individuals and declined linearly with increasing age. Elevated tHcy independently increases odds of prevalent stroke. Younger individuals and those with concomitant hypertension may particularly benefit from tHcy-lowering. Copyright © 2010 Elsevier B.V. All rights reserved.