High mobility group I-C (HMGI-C) protein is a non-histone DNA-binding factor that organizes active chromatin. This protein is expressed during the limited phase of embryonic development and may regulate the expression of genes critical for embryonic cell growth and differentiation. As embryonic mechanisms are also known to play a role in the development of some neoplasms, we investigated human brain tumors for the expression of HMGI-C to determine its role in the differentiation of glial cell tumors. Immunohistochemical analysis revealed HMGI-C in all of the low-grade astrocytomas, in 2 of 3 anaplastic astrocytomas (grade 3), but in only one of 8 glioblastomas. The results were confirmed at the mRNA level by nested reverse-transcription polymerase chain reaction analyses. Loss of HMGI-C was also demonstrated in a case of glioblastoma transformed from the low-grade astrocytoma strongly expressing HMGI-C protein. These results suggest that HMGI-C may be involved in the differentiation of glial tumor cells, and that loss of HMGI-C expression may contribute to the transformation of low-grade astrocytoma into glioblastoma.