Multiple Sclerosis (MS) is characterized by motor, cognitive, and neuropsychiatric symptoms, which can occur independently. While MS is traditionally considered an inflammatory disease of the white matter, degeneration of gray matter is increasingly recognized as an important contributor to the progressive cognitive decline. A protective factor against the progression of cognitive dysfunction in MS could be the cognitive reserve, defined as resistance to brain dysfunction. Aim of the present study is to evaluate the role of cognitive reserve for different aspects of cognitive dysfunction of patients with MS. We found that patients with MS and lower cognitive reserve have poorer neuropsychological performance and slower information speed processing. These findings support the notion that intellectual reserve may protect some aspects of cognitive function in patients with MS.