Background: Fatigue is a common symptom in individuals with multiple sclerosis (MS). To date, the pathophysiology of fatigue in MS remains ill-understood; however, converging evidence seems to suggest that a key factor in fatigue development might be the dysregulation of neuropsychological processes underpinning the evaluation of the rewarding outcomes of actions. Objectives: To explore the relationship between reward-related cognition and fatigue in MS and to explore the usefulness of reward perception testing to predict the efficacy of monoamine-modulating drugs on fatigue. Methods: The study included 104 fatigued and 70 fatigue-free Relapsing-Remitting MS patients. All subjects were screened for the lack of any significant mood, cognitive, or personality disorders that could confound results. The different facets of the motivation system such as the patient's reward perception were assessed at baseline using the Behavioural Inhibition and Behavioural Activation Scales (BIS/BAS). Fatigue was assessed with the Modified Fatigue Impact Scale (MFIS). Fatigue values after three months of therapy with escitalopram or bupropion were correlated with those baseline BIS/BAS scores. Results: Fatigued patients demonstrated lower reward responsiveness compared to fatigue-free subjects. Reward responsiveness scores were found to be associated with baseline MFIS scores and with fatigue reduction after treatment with bupropion: Lower reward responsiveness at baseline predicted higher fatigue remission rates in bupropion-treated patients, as compared with escitalopram-treated patients. Discussion: Reward responsiveness was linked with MS-related fatigue and might represent one of its key cognitive underpinnings. Our results suggest that evaluation of reward responsiveness could provide useful information to guide individualized therapy of MS-related fatigue. © The Author(s) 2012.