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Background: Age is a well-known risk factor for both stroke and increased burden of white matter hyperintensity (WMH), as detected on magnetic resonance imaging (MRI) scans. However, in patients diagnosed with ischemic stroke (IS), WMH volume (WMHv) varies significantly across age groups. We sought to examine the determinants of WMH burden across the ages of stroke onset with the goal to uncover potential age-specific stroke prevention targets., Methods: Adult subjects from an ongoing hospital-based cohort study of IS patients with admission brain MRI were categorized as having early (<55 years), late (>75 years), or average (55-75 years) age of stroke onset. WMHv was measured using a previously validated, MRI-based semi-automated method and normalized for linear regression analyses., Results: Of 1008 IS subjects, 249 had early-onset stroke (24.7%), and 311 had late-onset stroke (30.9%). In multivariable analysis of WMHv using backward stepwise selection, only age (β = .02, P = .018), hypertension (β = .24, P = .049), and history of tobacco use (β = .38, P = .001) were independently associated with WMHv in patients with early-onset stroke, whereas male sex (β = -.30, P = .007), hyperlipidemia (β = -.27, P = .015), and current alcohol use (β = .23, P = .034) were independently associated with WMHv in patients with late-onset stroke., Conclusions: History of tobacco use is a strong independent predictor of WMH burden in patients with early-onset stroke, whereas age is no longer associated with WMHv in IS patients older than 75 years of age. These findings suggest that the major risk factors to target for stroke prevention differ across age groups and may be modifiable., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)