Background White matter hyperintensity (WMH), a common radiographic finding associated with stroke risk and outcome, has been linked to matrix metalloproteinase (MMP) activity and increased levels of oxidative stress in nonstroke populations. We sought to determine whether WMH severity is associated with plasma levels of MMPs and oxidative stress (F2-isoprostane) in subjects with acute ischemic stroke (AIS). Methods We measured plasma biomarker levels at baseline and 48 hours in consecutive AIS subjects. White matter hyperintensity volume (WMHv) was quantified on admission magnetic resonance imaging using a validated semiautomated protocol, and Spearman correlation coefficients were derived for all measured biomarkers. Results We enrolled 405 AIS subjects (mean age 70 ± 15 years; 58% male; median WMHv 3.4 cm3 , interquartile range 1.4-9.5). WMHv and age were strongly correlated (ρ = .57, P  < .0001). WMHv and MMP-2 levels were correlated at baseline (ρ = .23, P  < .0001) and at 48 hours poststroke (ρ = .19, P  = .002). In multivariate analysis, 48-hour MMP-2 levels were independently associated with WMHv (β = .12, P  = .04). MMP-9 and F2-isioprostane levels did not correlate with WMHv. Conclusions In AIS patients, MMP-2 levels are associated with the pre-existing burden of WMH. If validated, these findings may further elucidate the role of MMP-2 in pathophysiology of chronic cerebrovascular injury, such as WMH, and in brain susceptibility to acute ischemia.