Oligodendrogliomas are the second most common type of glial neoplasm with distinct prognostic and therapeutic implications. Although refinements have led to improved clinical stratification, current grading schemes are still limited by subjective histopathological criteria. In this report, we have used oligonucleotide array technology to perform expression profiling in morphologically classic oligodendrogliomas. Expression information from approximately 1100 genes divided tumors into two molecularly distinct groups that corresponded exactly to their previously assigned histological grades. Subsequent gene clustering identified a subset of 196 transcripts showing a common, differential expression pattern between tumor grades. A number of these genes have been associated with the maintenance of cytoarchitecture, cellular differentiation and maturation, immunogenicity, and chemotherapeutic resistance. These results demonstrate the utility of gene expression profiling as an objective, ancillary tool for grading oligodendrogliomas and a potential approach for classifying diffuse gliomas where histological assessment may be difficult or ambiguous.