AIM: The clinical aim was to provide up-to-date evidence-based recommendations for the treatment of MS-related fatigue (MSRF). The scientific aim was to prioritise topics for future randomised clinical trials with sufficient power. METHODS: A systematic search of review based research that considered MSRF in adults (18years and over) was undertaken in May 2016. Data from reviews was extracted, critically appraised and synthesised using four specific techniques. RESULTS: A total of 24 reviews were identified (17 non-pharmacological, 5 pharmacological, 2 combining both), which contained 339 studies on interventions deigned to improve MSRF. The methodological quality of the reviews was identified by an average AMSTAR score of 6.5 (SD=1.87: 95% CI=5.75-7.25). No pharmacological intervention had strong evidence for improving MSRF. Limited/conflicting evidence was found for Amantadine and Prokarin and potential benefits for Modafinil were identified. Pemoline and Carnitine contained unclear/no evidence for fatigue management. Non-pharmacological interventions produced mixed conclusions regarding the effectiveness of the intervention to improve MSRF. Education (energy conservation and fatigue management) and exercise had supporting evidence for reducing MSRF but mixed conclusions gathered from subtypes of exercise. Reviews considering psycho-behavioural interventions (CBT and mindfulness) had limited information considering effectiveness. Finally, a single intervention combining physical and cognitive strategies showed more promising results. CONCLUSION: Further research into Pharmacological interventions for MSRF is required notably considering the potential of Modafinil. Yoga and energy conservation/fatigue management programs had strong evidence supporting use in management of MSRF. Due to the dissimilar interventions used in combined training the subtype of exercise cannot be recommended. Future research into Amantadine, psycho-behavioural interventions is vital to justify the current National Institute for Health and Care Excellence guidelines. The methodological quality of studies inhibited the ability of this review to provide other recommendations.