Purpose/Objective: To assess the efficacy of modafinil for the treatment of new learning and memory deficits and fatigue in multiple sclerosis. Only 1 previous study in the literature, to our knowledge, examined the effect of modafinil on cognition specifically in persons with multiple sclerosis. Research Method/Design: Sixteen patients with a diagnosis of multiple sclerosis (MS) and documented new learning impairment completed the study. In a 5-week randomized, double-blinded, crossover design, participants received either a single daily oral dose of modafinil (200 mg) or placebo for 2 weeks. A 1-week washout period was included between study arms. Results: No effect of modafinil was noted on learning and memory performance. Participants taking 200 mg of modafinil showed improvement in 1 of the 2 working memory measures administered, the Wechsler Adult Intelligence Scale-III (WAIS-III) Letter-Number Sequencing task, as compared with those on placebo. Treatment with modafinil did not have a beneficial effect in reducing self-reported fatigue. No changes were noted on the Modified Fatigue Impact Scale or the Fatigue Severity Scale with the treatment of modafinil, as compared with placebo. Conclusions/Implications: Findings indicate that 200 mg of modafinil has the potential to improve working memory in persons with MS. These findings suggest that modafinil may enhance aspects of cognition in persons with MS and may be an effective adjunct to clinical rehabilitation interventions.