We investigated motor network function in patients with benign multiple sclerosis (BMS) and contrasted the results with those obtained from patients with secondary progressive multiple sclerosis (SPMS) and healthy controls (HC) to elucidate better the factors associated with a favorable clinical evolution in multiple sclerosis (MS). Diffusion tensor (DT) and fMRI scans during the performance of a simple motor task were prospectively acquired from 17 patients with BMS, 15 patients with SPMS, and 17 HC. Patients with BMS and SPMS were matched for age, gender, and disease duration. DT MRI histograms of the normal-appearing white matter (NAWM) and gray matter (GM) were derived. fMRI analysis was performed using SPM5 (Wellcome Department of Cognitive Neurology, London, UK). Compared with HC, patients with BMS and SPMS had increased activations of the left primary sensorimotor cortex. Patients with SPMS also showed increased activations of the left secondary sensorimotor cortex, left inferior frontal gyrus (IFG), right hippocampus, and several visual areas. Compared with HC and patients with BMS, patients with SPMS had reduced activations of the left supplementary motor area, left putamen, and right cerebellum. Compared with patients with BMS, patients with SPMS had increased activations of the left IFG and right middle occipital gyrus. In patients with MS, fMRI changes were correlated with T2 lesion volumes and DT MRI changes in the NAWM and GM. This study shows that, contrary to what happens in secondary progressive multiple sclerosis, the movement-associated pattern of activations seen in benign multiple sclerosis resembles that of healthy people, and its abnormalities are restricted to the sensorimotor network. The long-term preservation of brain functional adaptive mechanisms in these patients is likely to contribute to their favorable clinical course.