Although several functional magnetic resonance imaging (fMRI) studies have shown adaptive cortical changes in patients with early multiple sclerosis (MS), the presence of brain plasticity and its role in limiting the functional consequences of brain tissue damage in patients with secondary progressive (SP) MS have not been fully investigated yet. In this study, we assessed the movement-associated brain pattern of cortical activations in patients with SPMS and investigated whether the extent of cortical brain activations is correlated with the extent of brain structural changes. From 13 right-handed SPMS patients and 15 sex- and age-matched healthy volunteers, we obtained: (a) brain dual-echo scans; (b) brain mean diffusivity and fractional anisotropy maps of the normal-appearing white (NAWM) and gray matter (NAGM); (c) fMRI during the performance of simple motor tasks [flexion-extension of the last four fingers of the right hand (task 1) and flexion-extension of the right foot (task 2)]. Compared to healthy volunteers, during task 1 performance, SPMS patients showed more significant activations of the ipsilateral inferior frontal gyrus, middle frontal gyrus, bilaterally, and contralateral intraparietal sulcus. During task 2 performance, SPMS patients had more significant activations of the contralateral primary sensorimotor cortex and thalamus and of the ipsilateral upper bank of sylvian fessure. For both tasks, strong correlations (r values ranging from -0.83 to 0.88) were found between relative activations of cortical areas of the motor network and the severity of structural changes of the NAWM and NAGM. This study demonstrates that cortical plasticity does occur in patients with SPMS and that it might have a role in limiting the clinical impact of MS-related damage. It also suggests that, in these patients, functional abilities are sustained by increased recruitment of highly specialized cortical areas.