BACKGROUND: Aim of this prospective longitudinal study was to identify static and dynamic O-(2-[18F]fluorethyl)-L-tyrosine PET (18FET-PET) derived imaging biomarkers in glioblastoma (GB) patients to obtain additional information concerning prognosis and monitoring of therapy. METHODS: 79 patients with newly diagnosed GB were included; 42 patients underwent stereotactic biopsy (unresectable tumors) and 37 patients microsurgical tumor resection. All patients were scheduled to receive radiotherapy plus concomitant and adjuvant temozolomide (RCx/TMZ). 18FET-PET evaluation using static and dynamic parameters was done prior to biopsy/resection, after resection, 4-6 weeks following RCx and after three cycles of TMZ. Endpoints were survival and progression-free-survival. Prognostic factors were obtained from proportional hazards models. RESULTS: Biological tumor volume before RCx (BTVpreRCx) was the most important 18FET-PET derived imaging biomarker and was independent of MGMT promoter methylation and clinical prognostic factors: patients with smaller BTVpreRCx had significant longer progression free (PFS) and overall survival (OS). 18FET time activity curves (TAC) before treatment and their changes after RCx were also related to outcome: patients with initially increasing TAC and those exhibiting a switch from decreasing to increasing TAC after RCx experienced longer progression-free-survival. CONCLUSIONS: BTVpreRCx and TAC represent important 18FET-PET-derived imaging biomarkers in GB. Increasing TAC are associated with prolonged PFS. The BTVpreRCx is a strong prognostic factor for PFS and OS independent of the mode of surgery. Our data furthermore suggest that patients harbouring resectable GB might benefit from maximal PET-guided tumor resection. SECONDARY CATEGORY: Clinical Neuro-Oncology.