<p>Osteoarthritis (OA) is the most prevalent joint disease worldwide and the leading cause of functional disability. Recent studies have shown alterations in gray matter (GM) volume in areas related to pain sensitivity and perception in patients experiencing chronic pain. These brain changes may be reversible once pain relief is obtained. This study aimed to compare brain volume measurements in patients with chronic pain due to knee OA with healthy controls using brain magnetic resonance imaging (MRI) and voxel-based morphometric (VBM) analysis. Additionally, we aimed to correlate these findings with motor functional capacity and stiffness data. We selected 29 adults with severe knee OA and 28 healthy controls, matched for age and gender. All participants underwent MRI, and the images were processed and analyzed using the VBM method with the SPM 8 program. Predefined brain areas, including the insula, prefrontal cortex, dorsolateral cortex, ventrolateral cortex, temporal cortex, parietal cortex, cingulate gyrus, and thalamus, were selected for comparative analysis. We observed a reduction in GM volume in patients with knee OA pain compared to healthy controls in several regions, including the right and left anterior cingulate gyrus, right amygdala, hippocampus, parahippocampal gyrus, left amygdala, hippocampus, parahippocampal gyrus, right precuneus, and right insula. Additionally, we observed an increase in GM volume in the right and left orbitofrontal cortex and right superior temporal cortex. Our results support the hypothesis that knee OA-related pain is associated with region-specific volumetric brain alterations. Importantly, the observed increases in orbitofrontal and temporal GM volume may reflect compensatory neuroplasticity in response to chronic pain burden. These findings align with emerging models of brain compensation. Understanding these patterns may facilitate the development of prognostic and surrogate biomarkers for chronic pain and inform brain-targeted rehabilitation strategies.</p>