The histogenesis of oligoastrocytomas remains controversial, with some data arguing similarity of oligoastrocytomas to astrocytic tumors, and other data suggesting closer relationships with oligodendroglial neoplasms. Since the molecular genetic changes in astrocytomas differ from those of oligodendrogliomas, we characterized 120 astrocytic and oligodendroglial tumors, including 38 oligoastrocytomas, for genetic alterations that occur disproportionately between astrocytomas and oligodendrogliomas, i.e. TP53 gene mutations and allelic loss of chromosomes 1p, 17p and 19q. As previously reported, TP53 mutations were common in astrocytic gliomas, occurring in approximately half of WHO grade II and III astrocytomas, but in only 5% of WHO grades II and III oligodendrogliomas. Allelic losses of chromosomes 1p and 19q, however, were common in oligodendrogliomas (41% and 63%), but less frequent in astrocytomas (9% and 35%). Oligoastrocytomas showed TP53 mutations in 12/38 (32%) cases and allelic losses of chromosomes 1p and 19q in 52% and 70%, respectively. Most importantly, TP53 mutations and allelic losses on chromosomes 1p and 19q were inversely correlated in oligoastrocytomas (p < 0.011 and p < 0.019). These data suggest the existence of two genetic subsets of oligoastrocytomas, one genetically related to astrocytomas and the other genetically related to oligodendrogliomas. Histologically, those oligoastrocytomas with TP53 mutations were more often astrocytoma-predominant, while those with chromosome 19q loss were more often oligodendroglioma-predominant.