Background: The receptor for epidermal growth factor (EGF-R) has consistently been found expressed or overexpressed in human malignant glioma disease. Therapeutic targeting of the EGF-R has shown mixed responses which appear to be restricted by specific features of the tumor cells.Nimotuzumab binds preferentially to highly over expressing cells, a phase III trial was initiated to test efficacy in glioma. Methods: Nimotuzumab was tested in an open label, randomized, multicenter Phase III trial in patients with histologically confirmed, newly diagnosed glioblastoma. 12 consecutive weekly infusions of 400mg during standard radiotherapy with Temozolomide followed by biweekly infusions of 400mg arm A was randomized against standard radio chemotherapy alone arm B. Primary endpoint was PFS as determined by centralized neuro-imaging review. OS as secondary endpoint with quality of life, safety as additional parameters.MGMT and EGF-R were assessed where sufficient materials could be retrieved as well as tumor hypoxia. Results: Between 2007 and 2010, 149 patients were randomized and 142 were available for analysis. Stratification according to resection status resulted in 40 pts in the treatment arm and 41 in the control arm with residual tumor and 31 vs 30 pts without residual tumor. PFS: 12 month was 25.5% arm A vs 20.3% in arm B (p = 0.78) and OS: 679 days vs 596 days. For non - methylated MGMT the difference was most notable: OS arm A 28 pats: 19.6 months vs arm B 28 pats 15.0 months EGF-R amplification, gave no clear signal, neither was there a statistically significant treatment effect between with or without residual tumor. Tumor hypoxia does not appear to have predictive value in the overall group but possibly in subgroups.AEs and SAEs did not reveal a new specific toxicity profile beyond the known side effects from glioma treatment with current standard. Conclusions: Nimotuzumab shows a clear trend towards efficacy in MGMT non-methylated glioblastoma patients. Safety profile and indications for subgroup efficacy potentially justify focused evaluation of antibody therapy against glioblastoma.