OBJECTIVES: To assess clinical effectiveness of cognitive behavioural therapy (CBT) in patients with multiple sclerosis (MS) fatigue. METHODS: Embase® and Cochrane databases were searched up to June 2012 to identify randomised controlled trials published in English evaluating effect of CBT (disseminated by any mode) in patients with MS fatigue. Eligibility of trials was assessed by two reviewers with any discrepancy reconciled by a third, independent reviewer. To compare CBT with other therapies, random-effect meta-analysis was conducted using Stata® (v11.1) on change from baseline to endpoint in fatigue score. RESULTS: Four studies of 107 retrieved citations met pre-defined inclusion criteria. Two studies compared CBT to no therapy and one study each compared CBT to relaxation therapy (RT) and supportive-expressive group therapy (SEGP). All studies were well conducted and no significant differences were observed between treatment groups for demographic characteristics. Weighted mean difference (WMD) demonstrated statistically significant reduction for change in fatigue score at 2 months from baseline with CBT versus no therapy (-7.04; p<0.001). When CBT was compared to RT, WMD was -4.29 (p<0.001) at 2 months, -2.74 (p=0.013) at 5 months, and -2.74 (p=0.027) at 8 months indicating that CBT group improved significantly on fatigue than RT group and this improvement was sustained over a period of time. Further, when CBT was assessed against SEGP, WMD was -12.2 (p=0.024) at 4 months, indicating that CBT (individualised therapy) demonstrated significantly better reduction in fatigue compared to SEGP (group therapy). CONCLUSIONS: Overall results demonstrated that CBT was significantly superior in alleviating fatigue compared to no therapy, RT, and SEGP. CBT appears to be promising, acceptable and clinically beneficial approach that could potentially benefit patients with MS fatigue in future. Thus, further research is warranted to determine which aspects of CBT are most effective and the optimal delivery of CBT for MS fatigue.