Purpose <p>Although neuroinflammation may play a key role in the pathology of migraine and its progression to chronic migraine (CM), its specific involvement-particularly the role of microglia- remains unclear. We investigated whether neuroinflammation is involved in the pathophysiology of CM and whether pro-inflammatory signals are associated with its clinical features.</p> Methods <p>Nineteen individuals with CM and 10 healthy controls (HCs) underwent integrated brain positron emission tomography (PET)/magnetic resonance (MR) using the translocator protein (TSPO) radioligand ([¹¹C] PBR28, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokine/chemokine. Volumes in regions of interest (ROI) were calculated based on MRI data and the standardized uptake value ratio (SUVR) for [¹¹C] PBR28 was extracted for each ROI. The Spearman’s rank correlation coefficient between [¹¹C] PBR28 SUVR and changes in plasma factors was calculated.</p> Results <p>CM patients had a significantly higher Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA) scores than that in HCs (<i>p</i> &lt; 0.05). Participants with CM also exhibited reduced volume in the thalamus <i>(p =</i> 0.012), compared with HCs. Moreover [11C] PBR28 binding was increased in the midbrain, occipital lobe and vermis, along with increased interictal plasma interleukin-8 (IL-8) and CX3CL1 levels, in individuals with CM compared with HCs. Notably, the midbrain levels of TSPO were negatively correlated with the headache frequency <i>(</i><i>r</i>=-0.462, <i>p =</i> 0.046).</p> Conclusions <p>These findings demonstrate increased central inflammation in CM participants compared to HCs, providing imaging evidence for the potential involvement of neuroinflammation in CM pathophysiology. Additionally, the observed reduction in thalamic volume may contribute to the chronification of migraine.</p> Clinical trial number <p>Not applicable.</p>