Astrocytomas, including the most malignant form, glioblastoma multiforme, are the most frequent and deadly primary tumors of the human nervous system. Recent molecular genetic analyses of astrocytomas have demonstrated frequent chromosome 17 deletions involving the telomeric region of the short arm (17p12-pter). This region contains a candidate tumor suppressor gene, TP53, which has recently been implicated in the etiology of a broad array of human cancers. To study the possible role of TP53 in astrocytoma development, 24 randomly chosen human astrocytic tumors were examined for genomic TP53 sequence aberrations using primer-directed DNA amplification in conjunction with direct sequencing. Five of the 11 grade III astrocytomas (glioblastoma multiforme), but only one of seven grade II astrocytomas (anaplastic astrocytoma) and none of either the grade I astrocytomas or oligodendrogliomas demonstrated distinct point mutations involving the TP53 gene. These data suggest that TP53 mutations may play a role in astrocytoma development and are predominantly associated with higher grade tumors.