Temozolomide (TMZ) has recently been recommended as a novel approach in the management of aggressive pituitary tumors. Herein, we present the case of a 43-year-old man with a 20-year history of silent subtype 2 pituitary corticotroph adenoma. Nine surgical resections and radiotherapy had failed to provide a cure. Morphological evaluation of the tumor revealed a mildly pleomorphic adenoma, the cells of which showed low-level cell proliferative activity with Ki67, increased topoisomerase II alpha index and conclusive O-6-methylguanine-DNA methyltransferase (MGMT) as well as vascular endothelial growth factor (VEGF) immunoreactivity. Given its aggressive behavior and failure of conventional therapy, TMZ was administered. The treatment was continued even after MGMT immunopositivity was identified, but failed to decrease MGMT immunoexpression and exerted no morphologic effect. Examination of the lesion after TMZ therapy showed neither morphologic nor immunohistochemical alterations. In our case, TMZ administration, despite changing the TMZ dosing regimen to prompt a drug response, was incapable of depleting MGMT stores.