OBJECTIVE In children with stroke, poor motor outcome is associated with early Wallerian degeneration of the corticospinal tract that is seen on diffusion-weighted MRI. In this study we test the hypothesis that early diffusion changes also occur in the corticospinal tract (CST) of adults after stroke and that these lesions are associated with poor outcome. METHODS In this retrospective study, we assessed images from a serial MRI study of adults with acute middle cerebral/internal carotid artery stroke. MRI-negative TIA patients served as controls. Custom software measured signal along the CST on different sequences, including the apparent diffusion coefficient (ADC). Visual detection of abnormal signal by blinded neuroradiologists was also evaluated. We then determined associations between CST signal changes and 3-month motor outcome (NIHSS score). RESULTS Thirty-eight patients (20 stroke/18 control) were included. ADC measures were much more accurate than other MRI sequences for detection of degeneration in the CST. The ADC decreased in a time-dependent fashion in the CST of patients with poor motor outcome but not in those with good outcome. Changes in ADC were maximal at 7 days. Neuroradiologists could visually detect these changes with accuracy comparable to the software method. CONCLUSIONS CST ADC decreases after acute stroke in patients with poor motor outcome and may represent early Wallerian degeneration. Recognition of this imaging marker may improve early outcome prediction and patient selection for rehabilitation and neuroprotection trials.