The oligodendrocyte myelin glycoprotein (OMgp) inhibits neurite outgrowth and axonal regeneration after brain injury, but its normal function remains unknown. Several observations suggest its implication in cell growth regulation. Here we report an analysis of the domain requirement in OMgp proliferation inhibitory function. We first studied the OMgp protein sequence in 14 mammal species and observed a high conservation of its leucine-rich repeat (LRR) domain. The deletion of this LRR domain is responsible for a total loss of function in an in vitro expression system. The possible three-dimensional structure of the LRR domain of OMgp was modelled using the structure of Yersinia pestis YopM cytotoxin as a template. The predicted arrangement of the LRR segments is compatible with a function of OMgp as a binding protein. The OMgp is a glycosylphosphatidyl-inositol-linked protein anchored in the plasma membrane of oligodendrocytes and neurones. Using deletion mutagenesis, we demonstrated the dispensability of the glycosylphosphatidyl-inositol anchor for OMgp proliferation inhibition function. Our results suggest that OMgp is part of a receptor complex, either as a coreceptor or as a membrane-bound or soluble ligand, involved in the transmission of a growth suppressive signal.