Diffusion-weighted magnetic resonance imaging detects ischemic injury within minutes after onset, and has been used to demonstrate drug efficacy in animal models of stroke. In 50 patients diagnosed with acute ischemic stroke (<24-hour duration) within the middle cerebral artery territory, lesion volume was measured by diffusion-weighted imaging. Thirty-four patients also had volumes measured by T2-weighted imaging chronically (median time, 7.5 weeks; mean, 15.9 weeks). Clinical severity was measured by the National Institutes of Health Stroke Scale Score and the Barthel index. Acute lesion volumes correlated with the acute stroke scale score (r = 0.56), the chronic stroke scale score (r = 0.63), and chronic lesion volumes (r = 0.84). Chronic volumes correlated with the chronic stroke scale score (r = 0.86) and the Barthel index (r = -0.60). When only cortically based lesions were considered, the correlations relating acute lesion volume measured by diffusion-weighted imaging (r = 0.61) and chronic lesion volume measured by T2-weighted imaging (r = 0.90) to the chronic stroke scale score were higher. These results provide evidence that lesion volumes determined by diffusion-weighted imaging acutely may be predictive of clinical severity and outcome, and may support a role for diffusion-weighted imaging in the assessment of acute stroke therapies in clinical trials.