© 2020 European Pain Federation - EFIC® Background: Cognitive Functional Therapy (CFT) is a physiotherapist-led individualized intervention for people with people with non-specific chronic low back pain (CLBP), involving biopsychosocial pain education, graded movement exposure and lifestyle coaching. Methods: A multicentre randomized controlled trial (RCT), including 206 participants with CLBP in Ireland, supported CFT¿s effectiveness for reducing disability, but not pain, compared to a group exercise and education intervention. In this study, causal mediation analysis was used to determine whether the effect of CFT on disability and the lack of effect on pain (relative to a group exercise and education intervention) is mediated by certain psychological and lifestyle factors. Hypothesized mediators measured were pain self-efficacy, stress, fear of physical activity, coping, depression, anxiety and sleep, at 6 months. The outcomes measured were functional disability and pain intensity at 12 months. Results: This causal mediation study shows that the majority of benefit of CFT (relative to a group exercise and education intervention) for disability is due to increasing pain self-efficacy. Conclusion: Conclusion: CFT did not improve the majority of the hypothesized mediators (stress, fear of physical activity, coping, depression, anxiety and sleep) and these mediators were not associated with either disability or pain. Unfortunately, the proportion of missing data in this study is substantial and these findings can only be considered hypothesis-generating. Therefore, future research should examine replicating the results of this study to verify the role of self-efficacy and other proposed mediators (e.g. stress, coping, sleep, fear) on clinical outcomes. Significance: An exploration of seven potential mediators was undertaken to determine the effect of Cognitive Functional Therapy (CFT) on disability and pain intensity in individuals with chronic low back pain compared to a group exercise and education intervention. CFT improved pain self-efficacy, which was associated with disability and pain outcomes. CFT did not improve the other six potential mediators (stress, fear of physical activity, coping, depression, anxiety and sleep) and these were not associated with disability or pain. The proportion of missing data in this study is substantial and these findings should be considered hypothesis-generating only.