The CD200 ligand is expressed by a variety of cell types, including vascular endothelia, kidney glomeruli, some subsets of T and B cells, and neurons in the brain and periphery. In contrast, the receptor of CD200, CD200R, has a limited expression pattern and is mainly expressed by cells of myeloid origin. A recently solved crystal structure of the CD200-CD200R ectodomain complex suggests involvement of the first immunoglobulin (Ig)-like modules in ligand-receptor binding, resulting in the inhibition of myeloid cell function. In the central nervous system, CD200 has been implicated in the suppression of microglia activation. We for the first time demonstrated that CD200 can interact with and transduce signaling through activation of the fibroblast growth factor receptor (FGFR), thereby inducing neuritogenesis and promoting neuronal survival in primary neurons. CD200-induced FGFR phosphorylation was abrogated by CD200R, whereas FGF2-induced FGFR activation was inhibited by CD200. We also identified a sequence motif located in the first Ig-like module of CD200, likely representing the minimal CD200 binding site for FGFR. The FGFR binding motif overlaps with the CD200R binding site, suggesting that they can compete for CD200 binding in cells that express both receptors. We propose that CD200 in neurons functions as a ligand of FGFR.