The functional implications of central motor impairment and peripheral muscle alterations in multiple sclerosis are unclear. Muscle strength, central and peripheral activation, and symptomatic fatigue were investigated in 16 patients with multiple sclerosis (MS) and 18 control subjects. Voluntary and electrically stimulated isometric contractions were obtained from the ankle dorsiflexor muscles. Maximal voluntary contraction (MVC) was 27% lower in MS patients than controls, although electrically stimulated force was similar. Muscle fat-free cross-sectional area (CSA) was similar in both groups. These data indicate central activation impairment in MS. Such impairment in MS was further demonstrated by decreased foot-tap speed, rate of voluntary force development, and central activation ratio. Peripheral activation changes in MS patients were modest. Although stimulated tetanic force was similar, force relaxation was slower in MS patients compared to controls, resulting in a left-shifted force-frequency relationship in MS. Motor function changes were not associated with fatigue but were associated with impaired ambulation. Thus, weakness and walking impairment, but not fatigue, were related to impaired central activation in MS. These findings may help optimize rehabilitation strategies designed to improve function in persons with MS.