The majority of patients with multiple sclerosis (MS) report fatigue that is often chronic and interferes with daily life. Although fatigue in MS is poorly understood, cognitions and behaviours in relation to symptoms and fatigue appear to play a role in the maintenance of MS fatigue. An intervention was developed on the basis of a cognitive-behavioural model of MS fatigue. The efficacy of this cognitive behaviour therapy (CBT) was tested in a randomised controlled trial. CBT resulted in a greater reduction in MS fatigue than relaxation training directly following treatment. In this study the data of this RCT were reanalysed to address the following questions: 1) Does CBT lead to significant change in the cognitions and behaviours hypothesised to perpetuate MS fatigue when compared to relaxation therapy? 2) Do any of these cognitive-behavioural variables mediate the effect of CBT on MS fatigue? Method 70 patients were randomised to CBT (n=35) or relaxation training (n=35). Patients completed the Cognitive and Behavioural Responses to Symptoms Questionnaire, the Brief Illness Perception Questionnaire (B-IPQ) which was modified to measure beliefs about fatigue, and the Fatigue Scale, pre-and post-therapy. Multiple mediation analysis using bootstrapping was used to determine which of the variables mediated the change in fatigue brought on by CBT.