Multiple sclerosis (MS) may present with diverse symptoms, with fatigue being common and disabling. Cognitive behavioural therapy (CBT) is a treatment used for different medical conditions. We aim to assess the efficacy of CBT and derivatives in reducing short- and long-term fatigue in adults with MS. 

We searched Medline, Embase, Web of Science, CENTRAL, and ClinicalTrials.gov up to September 1, 2025, for randomized controlled trials (RCTs) comparing CBT and derivatives with pharmacological, non-pharmacological treatments, or control groups (waiting lists or usual care). Outcomes included short- and long-term fatigue (≤10 or >10 weeks respectively), adverse events, and quality of life. We used the Cochrane Risk of Bias 2 tool to assess bias risk, performed meta-analyses with risk ratios (RR) for dichotomous outcomes and standardized mean differences (SMD) for continuous outcomes, and applied the GRADE approach to rate the certainty of evidence.

We included 20 studies enrolling 2,696 participants. Seventeen studies contributed to the primary comparison meta-analysis (CBT versus control groups). Most studies had an overall high risk of bias. Using random-effects models, CBT showed a reduction in short-term fatigue (SMD -0.59, 95%CI: -0.99 to -0.18) but not in long-term fatigue (-0.10, 95%CI: -0.26 to 0.40), with a very low certainty. CBT resulted in no clinically meaningful difference in adverse events (RR, 0.82; 95%CI, 0.45-1.51; very low certainty). CBT may have little to no effect on quality of life (SMD 0.15, 95%CI -0.09 to 0.39), with very low certainty.

The included RCTs suggest CBT may have limited or uncertain effects on fatigue, quality of life, and adverse events, with high bias risk, imprecision, and inconsistency. Future research should address these study limitations to understand better CBT's role in managing MS fatigue.