Myelin/oligodendrocyte glycoprotein (MOG) is an integral membrane protein expressed on the oligodendrocyte cell surface and the outermost surface of myelin sheaths. Due to this localization, MOG is a primary target antigen involved in immune-mediated demyelination. We previously reported that MOG is a unique member of the immunoglobulin (Ig) superfamily in that it possesses two large hydrophobic domains. MOG is highly conserved between deduced peptide sequences of rodent and human MOG (approximately 89% identity). We have completed an investigation of alternative splicing within the human and mouse MOG genes. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of total cellular RNA isolated from both fetal and adult human central nervous system (CNS) tissues reveals a complex array of alternatively spliced MOG-specific variants and the presence of two novel exons. Exon 3 encodes a short hydrophilic domain containing multiple in-frame termination codons that would result in truncation of MOG prior to translation of its transmembrane domain. Exon 7 encodes an additional hydrophilic domain that replaces MOG's second hydrophobic domain in one splice variant. We also observed that five of our eight MOG variants exhibited an alternative internal 3' splice acceptor within MOG's terminal exon. Surprisingly, no splicing was observed in a developmental study using mouse brainstem RNA.