Background: Multiple sclerosis (MS) is an inflammatory disorder of the brain and spinal cord. Disability status and progression are associated with reduced physical activity (PA) and cardiovascular function. Lack of adequate PA combined with inflammation may create high susceptibility to subclinical atherosclerosis and vascular dysfunction. Purpose: The purpose of this study was to compare subclinical atherosclerosis and arterial function between individuals with and without MS matched for age, sex, and body mass index. Methods: Thirty-three individuals diagnosed with MS and 33 controls underwent strain gauge plethysmography for resting forearm blood flow (FBF) and peak reactive hyperemia for the microvascular function. Intima-media thickness and arterial compliance (AC) were measured using carotid ultrasound for vascular function. C-reactive protein and PA (7-d accelerometer data) were also measured. Results: There was a significant difference (P G 0.05) in resting FBF, peak reactive hyperemia, central pulse wave velocity, and AC between the MS and control groups. PA was associated with peak FBF and central pulse wave velocity but not FBF and carotid AC. Individuals with MS exhibit reduced arterial function but similar intima-media thickness compared with controls. Persons with MS had significantly reduced PA levels compared with controls, and PA accounted for differences in arterial function between groups. Conclusions: These results indicate that subclinical markers of atherosclerosis are higher in individuals with MS, suggesting a higher risk of cardiovascular disease in this population. However, the higher levels of subclinical atherosclerosis were accounted for by the low PA in persons with MS, suggesting that increasing PA may reduce the increase in cardiovascular disease risk in patients with MS. Copyright © 2012 by the American College of Sports Medicine.