O6-Methylguanine-DNA-Methyltransferase (MGMT) is a DNA repair protein considered to be a chemosensitivity predictor. We evaluated the immunohistochemical MGMT expression in 28 consecutive oligodendroglial tumors (21 oligodendrogliomas, 5 mixed oligoastrocytomas, and 2 glioblastomas with prominent oligodendroglial features; 13 treated with CCNU) and compared it with that of 13 glioblastomas. Twenty-six (93%) oligodendroglial tumors were MGMT-negative, 2 (7%) were MGMT-positive. Twelve (92%) patients treated with CCNU had MGMT-negative lesions and their median survival was 73 months; 1 patient had an MGMT-positive oligodendroglioma and is alive at 28 months. Three (23%) glioblastomas were MGMT-negative and 10 (77%) MGMT-positive. The lower MGMT expression in oligodendroglial tumors compared to glioblastomas (P < 0.05), which have different chemosensitivity, suggests a possible role of MGMT in the determination of chemoresistance. Nevertheless, the heterogeneous outcome of our MGMT-negative oligodendroglial tumors treated with CCNU, indicates that MGMT expression alone is insufficient to predict the response to alkylating drugs, presumably because of the numerous mechanisms involved.