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2036 Background: As recently demonstrated (Neurooncology, 2016), neurological decline of patients with brain cancer (high grade glioma, brain metastases) during radio(chemo)therapy (RCT) of the brain is oftentimes caused by CMV-encephalopathy but not disease progression or therapeutic complications. We examined the impact of clinical and serological CMV-status on the survival one year after the onset of radio(chemo)therapy of the brain. Methods: 118 patients requiring whole-brain radiotherapy for brain metastases (n = 55) or local RCT of the brain for high-grade gliomas (n = 63) were observed in the prospective GLIO-CMV-01 study. MRIs and blood samples were obtained before, halfway through, and at the end of radiotherapy. MRIs were screened for disease progression or increased intracranial pressure. Blood was tested for anti-CMV immunoglobulin (Ig)M, anti-CMV IgG, and CMV DNA. Results: 68 of 118 (58%) patients were positive for anti-CMV IgG before radio(chemo)therapy. 28 of those 68 (41%) developed CMV-viremia during or up to 28 days after the end of irradiation. 21 of those 28 (75%) required treatment for symptomatic CMV-associated encephalopathy. One year after the start of RCT, survival was 72% (34/47) (no encephalopathy, anti-CMV-IgG+) or 68% (34/50) (no encephalopathy, anti-CMV-IgG-) versus 38% (8/21) (encephalopathy) (p = 0.0034). Conclusions: Symptomatic CMV-encephalopathy all but doubles the mortality of brain cancer patients within one year of RCT, despite antiviral treatment with ganciclovir. These findings heavily underline the importance to identify patients with increased risk profile for developing CMV-encephalopathy before initiating RCT.