Methods. A randomised controlled trial (RCT) was carried out to evaluate the effectiveness of a 12-week multicomponent treatment based on Pain Neuroscience Education, therapeutic exercise, Cognitive Behavioural Therapy and Mindfulness Training, in addition to Treatment As Usual (TAU), compared with TAU only in patients with Fibromyalgia (FM). Data were collected on the Revised Fibromyalgia Impact Questionnaire (FIQR) (primary outcome), and pain, fatigue, kinesiophobia, physical function, anxiety, and depressive symptoms (secondary outcomes) at baseline, at 12 weeks and, for the multicomponent group only, at six and nine months. An intention to treat (ITT) approach was used to analyse between-group differences. The effect size (Cohen's d) was reported for each pairwise comparison. Differences in baseline variables between responders (> 20% FIQR reduction) and non-responders were compared using the Student's t-test (quantitative variables) and χ²-test (categorical variables). Results. A total of 272 patients with FM were randomly assigned to either the multicomponent group (n = 135), who received the multicomponent treatment plus TAU or the TAU group (n = 137), who received TAU alone. Significant differences (p < .001) with a large effect size (Cohen’s d > 0.80) between the multicomponent group and TAU group were found for functional impact, pain, kinesiophobia, and physical function, whilst differences with a moderate size effect (Cohen’s d > 0.50 and < 0.80) were found for fatigue, anxiety, and depressive symptoms. For all the baseline variables the non-responders showed a low effect size for depressive symptoms (Cohen’s d < 0.50). The number needed to treat (NNT) was 2 (95%CI 1.7 - 2.3).Conclusions. These results indicate that, when compared with TAU, this multicomponent treatment leads to beneficial effects in improving FM-related symptoms.Impact statement. ●This is the first study showing the beneficial effects of a multicomponent treatment that specifically integrates PNE in patients with Fibromyalgia.●This work provides new and useful information to promote a paradigm shift in the management of both FM and chronic pain.