BACKGROUND Vascular cell adhesion molecule-1 (VCAM-1) is a well-known biomarker of endothelial activation. This study aimed to determine whether changes in peripheral VCAM-1 levels occurred in major depressive disorder (MDD) patients and explored immune-brain interactions based on neuroimaging. METHODS This study included 165 subjects (80 healthy controls [HCs] and 85 MDD patients). Of them, 133 underwent magnetic resonance imaging. VCAM-1 was measured using a commercially available Enzyme-Linked Immunosorbent Assay kit following the manufacturer's instructions. The gray matter volume (GMV) and surface-based functional connectivity (FC) were calculated based on Schaefer parcellation 400 parcels. RESULTS Compared with the HCs, MDD patients exhibited significantly higher level of VCAM-1. The correlation analysis showed that VCAM-1 had a significant negative correlation with GMV of the right medial frontal cortex (MFC) and postcentral (PostCG). The mediation analyses showed that VCAM-1 mediated the association between group and GMV of PostCG and the FC of left ventral prefrontal cortex (vPFC) with right inferior parietal lobe (IPL). CONCLUSIONS This study showed that a high level of VCAM-1 was associated to the decreased GMV in the right MFC and PostCG, and mediated the FC of the left vPFC with right IPL. These findings suggested that VCAM-1 might contribute to the etiology of MDD by influencing brain structure and function. CONCLUSIONS The cross-sectional design makes it difficult to determine the causal relationship and dynamic effect among VCAM-1, brain structure/function features, and depressive symptoms.