CD97 is a recently identified seven-span transmembrane (7-TM) protein that is expressed by leukocytes early after activation. CD97 binds to its cellular ligand CD55 (decay accelerating factor), which protects several cell types from complement-mediated damage. The functional consequences of CD97-CD55 binding are largely unknown, but previous data imply that CD97-CD55 interactions play a role in cellular activation, migration, and adhesion under inflammatory conditions. Here we examined the expression of CD97 and CD55 by immunohistochemistry in multiple sclerosis (MS). On the basis of established criteria for inflammation and demyelination, different lesion stages were distinguished in MS post-mortem brain tissue. In normal white matter, CD97 expression was not found, but CD55 was expressed with weak staining intensity on endothelial cells. In pre-active lesions, defined by abnormalities of the white matter, many infiltrating T cells, macrophages (MPhi) and microglia expressed CD97. CD55 was highly expressed by endothelial cells. In active lesions with myelin degradation, MPhi and microglia expressed both CD55 and CD97. Furthermore, a sandwich ELISA showed significantly (p<0.05) elevated levels of soluble CD97 in serum but not in cerebrospinal fluid of MS patients (37%) compared to healthy controls (8%).Collectively, these data suggest that CD97-CD55 interactions are involved in the inflammatory processes in MS. CD55, which is expressed in lesions by vessels to protect against complement-mediated damage, might bind to CD97 on infiltrating leukocytes. This interaction may facilitate cell activation and migration through the blood-brain barrier. In addition, CD97-CD55 interactions in the parenchyma of the brain may contribute to the inflammation.