Abstract Background: The role of apolipoprotein E (APOE) polymorphism has been well recognized in other cognitive neurodegenerative disorders, such as Alzheimer disease. Its role in multiple sclerosis (MS) is less clear, though studies indicate that 40% to 60% of patients with MS have evidence of cognitive impairment. Objective: To determine whether there is an association between APOE 4 and cognitive deficits in MS. Methods: We performed a standardized battery of neuropsychological tests investigating the four cognitive domains commonly impaired in MS and assessed the association of the presence of APOE 4 with cognition in MS. Results: A strong association was found between the presence of APOE 4 and cognitive deficits in patients with MS, particularly in the domains of learning and memory. This association was strongest in our youngest cohort (age 31 to 40) of patients with MS. Conclusions: APOE 4 is significantly associated with cognitive impairment in patients with multiple sclerosis (MS). However, the modest effects do not justify APOE genotyping of patients with MS in clinical practice.