Background: The elderly patients with glioblastoma have an extremely poor prognosis. As they often have some degree of age-related vulnerability, it is especially important to minimize a risk of treatment-related adverse events by optimizing treatment intensity for this population. We conducted phaseⅡ clinical trial to investigate the efficacy of stratified monotherapy approach according to O6-methylguanine-DNA methyltransferase (MGMT) methylation status in elderly patients with glioblastoma. Methods: Patients aged 70 years or older with Karnofsky performance status (KPS) of at least 60 were eligible for this study. MGMT methylation status was quantitatively assessed by pyrosequencing based on the average methylation ratio of 16 CpG sites in the MGMT gene promoter. The patients with highly methylated MGMT promoter defined as an average methylation ratio with 30% or higher were treated with temozolomide (TMZ) monotherapy (standard 5/28 regimen), while the others with low or intermediate levels of MGMT promoter methylation were treated with radiation therapy (40Gy/15fr) alone. Results: Between April 2013 and December 2017, 70 patients were enrolled in this study. Median age was 78 years (70-91) and median KPS was 60 (60-100). Of 70 patients, 19 patients with highly methylated MGMT promoter received TMZ monotherapy, while the remaining 51 patients were treated with radiation therapy. Median progression-free survival (PFS) and median overall survival (OS) were 7.5 and 17.4 months in the TMZ group, respectively. Median PFS and median OS were 4.6 and 10.4 months in the radiotherapy group, respectively. Conclusions: For elderly glioblastoma patients with highly methylated MGMT promoter, TMZ monotherapy could be a treatment option. Clinical trial information: UMIN000012172.