Myelin oligodendrocyte glycoprotein (MOG) is a myelin-specific protein restricted to the central nervous system (CNS). While MOG is considered a putative autoantigen in MS, its function(s) in myelin is unknown. As CNS myelin is able to activate the classical complement pathway, it must contain a Clq-binding/activating protein but the identity of this protein has not been reported. The data in this paper clearly demonstrate that MOG specifically binds Clq in a dose-dependent and saturating manner. This calcium-dependent interaction is mediated by the extracellular immunoglobulin-like domain of MOG. This MOG domain contains an amino acid motif similar to the core Clq-binding sequence previously identified in IgG antibodies. Purified MOG also inhibited the antibody-dependent lysis of RBC by complement. Taken together, these results demonstrate that MOG binds Clq near the IgG binding site and may be the protein responsible for complement activation in myelin. This direct interaction between a myelin-specific protein and Clq has significant implications for CNS inflammation and could be particularly important in demyelinating diseases such as multiple sclerosis.