Motor practice is an important component of neurorehabilitation. Imaging studies in healthy individuals show that dynamic brain activation changes with practice. Defining patterns of functional brain plasticity associated with motor practice following stroke could guide rehabilitation. The authors aimed to test whether practice-related changes in brain activity differ after stroke and to explore spatial relationships between activity changes and patterns of structural degeneration. They studied 10 patients at least 6 months after left-hemisphere subcortical strokes and 18 healthy controls. Diffusion-weighted magnetic resonance imaging (MRI) was acquired at baseline, and functional MRI (fMRI) was acquired during performance of a visuomotor tracking task before and after a 15-day period of practice of the same task. Smaller short-term practice effects at baseline correlated with lower fractional anisotropy in the posterior limbs of the internal capsule (PLIC) bilaterally in patients (t > 3; cluster P < .05). After 15 days of motor practice a Group × Time interaction (z > 2.3; cluster P < .05) was found in the basal ganglia, thalamus, inferior frontal gyrus, superior temporal gyrus, and insula. In these regions, healthy controls showed decreases and patients showed increases in activity with practice. Some regions of interest had a loss of white matter connectivity at baseline. Performance gains with motor practice can be associated with increased activity in regions that have been either directly or indirectly impaired by loss of connectivity. These results suggest that neurorehabilitation interventions may be associated with compensatory adaptation of intact brain regions as well as enhanced activity in regions with impaired structural connectivity.