Objective To determine the relative efficacy of amantadine, pemoline, and placebo in treatment of multiple sclerosis (MS)-related fatigue. Background Fatigue is a complication of MS. Both pemoline and amantadine have been used to treat MS fatigue, but their relative efficacy is not known. Methods Amantadine, pemoline, and placebo were compared in a randomized, double-blind, placebo-controlled study using a parallel-group design. Ninety-three ambulatory MS patients completed the study. Primary outcome measures were the fatigue seventy scale (FSS); the MS-specific fatigue scale (MS-FS); and subjective response determined by verbal self-report. Secondary outcome measures consisted of assessments of sleep, depression, and vitality. Repeated-measures analysis of variance with planned post-hoc contrasts and Fisher's exact test were used to compare treatment response. Results Amantadine-treated patients showed a significantly greater reduction in fatigue, as measured by the MS-FS, than did patients treated with placebo (p = 0.04). By verbal report at the end of the study, 79% of patients treated with amantadine versus 52% treated with placebo and 32% treated with pemoline preferred drug therapy compared with no treatment (p = 0.03). No significant differences in any primary outcome measures were noted between pemoline and placebo. Neither amantadine nor pemoline affected sleep or depression relative to placebo. Conclusion Amantadine was significantly better than placebo in treating fatigue in MS patients, whereas pemoline was not. The benefit of amantadine was not due to changes in sleep, depression, or neurologic disability.