Fibromyalgia (FM) is a disabling syndrome characterized by chronic pain associated with fatigue. Its pathogenesis is unknown, but alterations in central sensitization, involving an imbalance of brain-derived neurotrophic factor (BDNF) and inflammatory biomarkers, appear to be implicated. The aim of this study was to evaluate the impact of attachment-based compassion therapy (ABCT) on levels of BDNF, the inflammatory markers TNF-α, IL-6, IL-10, and the C-reactive protein (CRP), analysing whether biomarkers play a mediating/moderating role in improvements in FM functional status. Thirty-four female patients with FM participated in a RCT and were assigned to ABCT or relaxation therapy. Blood extractions were conducted at baseline and post-intervention, with self-report assessments of functional status (FIQ) at baseline, post-intervention and 3-month follow-up. A pro-inflammatory composite was obtained by summing up IL-6, TNF-α and CRP normalized values. Non-parametric tests, analysis of variance and regression models were used to evaluate treatment and mediation/moderation. Compared to relaxation therapy, ABCT showed significant improvements in FIQ and decreases in BDNF, CRP, and pro-inflammatory composite. Changes in BDNF had a mediating role in FIQ. ABCT seems to reduce BDNF and appears to have anti-inflammatory effects in FM patients. Reductions in BDNF could be a mechanism of FM functional status improvement. Clinical Trial Registration:http://ClinicalTrials.gov, identifier NCT02454244. Date: May 27th, 2015.