In the DIRECTOR trial, a 1:1 randomization was performed for temozolomide alternating weekly (120 mg/m² body surface area per day) and 21/28 days (80 mg/m² body surface area) with the aim of establishing superiority of temozolomide alternating weekly for the primary endpoint time to treatment failure. This is defined as time to progression, discontinuation of therapy due to toxicity, or death. In addition, aim was to determine the impact of O6-methylguanine-DNA methylatransferase promoter methylation status on study outcomes. In 16 centers in Germany, Austria, and Switzerland, 105 patients were randomized between 09/2009 and 06/2012. There were no statistically significant differences between the regimens. Methylation of the MGMT promoter was associated with progression-free survival at six months of 39.8% versus 6.9% in patients with unmethylated MGMT promoter. In conclusion, temozolomide restart for patients with methylated MGMT promoter is a reasonable therapy for glioblastoma progression.