We combined functional magnetic resonance imaging (fMRI) and diffusion tensor tractography to investigate the functional and structural substrates of motor network dysfunction in patients with primary progressive multiple sclerosis (PPMS). In 15 right-handed PPMS patients and 15 age-matched healthy controls, we acquired diffusion tensor magnetic resonance imaging and fMRI during the performance of a simple motor task. Tractography was used to calculate diffusion tensor-derived measures of the corpus callosum, the corticospinal tract, the optic radiation, the fronto-occipital fasciculus, and the inferior longitudinal fasciculus. Analyses of fMRI activations and functional connectivity were performed using statistical parametric mapping (cluster threshold of P = 0.001, and extent cluster threshold of 10 voxels for comparison of activations; P < 0.05, family-wise error corrected for functional connectivity). As compared with controls, PPMS patients had more significant activations of the left postcentral gyrus, left secondary sensorimotor area, left parahippocampal gyrus, left cerebellum, right primary sensorimotor cortex (SMC), right basal ganglia, right insula, right cingulum, and cuneus bilaterally. As compared with PPMS patients, controls had increased functional connectivity between the left primary SMC and the ipsilateral inferior frontal gyrus. Conversely, PPMS patients showed increased functional connectivity between the left primary SMC and the right cuneus. Moderate correlations were found between functional activations and damage to the tracts studied (r-values between 0.82 and 0.84; P < 0.001). These results suggest that, as compared with healthy controls, PPMS patients show increased activations and abnormal functional connectivity measures in several areas of the sensorimotor network. Such changes are correlated with the structural damage to the white matter fiber bundles connecting these regions.