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OBJECT Circulating microRNAs (miRNAs) are a new class of highly promising cancer biomarkers. Malignant glioma is one of the most devastating and lethal forms of intrinsic CNS tumor. Here, the authors evaluated serum miRNA 205 (miR-205) levels in patients with glioma. METHODS Sixty-four patients in whom glioma was diagnosed and 45 healthy controls were recruited between October 2011 and March 2012 and randomly assigned to the screening cohort or the validation cohort. Cohorts of patients with other brain tumors, including meningioma (n = 8), primary diffuse large B-cell lymphoma of the CNS (n = 6), and pituitary adenoma (n = 5), were investigated and compared. miR-205 extraction from serum was detected by real-time quantitative reverse-transcription polymerase chain reaction. The Kaplan-Meier method was applied to perform survival analysis, the risk factors were analyzed by using a Cox regression model, and the receiver operating characteristic working curve was used to analyze the value of miR-205 in the prognostic evaluation of the patients. RESULTS The authors first demonstrated that serum miR-205 expression was significantly lower in patients with glioma than in healthy controls (p < 0.001). It is important to note that serum miR-205 expression demonstrated a stepwise decrease with ascending pathological grades. The serum miR-205 biomarker had high sensitivity, specificity, and accuracy in patients with glioma. Serum levels of miR-205 were identified as an individual diagnostic marker and were significantly lower in the glioma cohort than in the other brain tumor cohorts. Serum miR-205 levels were significantly increased in postoperative samples over those in the preoperative samples and were reduced again during glioblastoma recurrences. Statistical analysis revealed a significant correlation between low serum miR-205 expression and both ascending pathological grades (p = 0.002) and low Karnofsky Performance Scale scores (p = 0.01). Patients with glioma at an advanced pathological grade (Grade III or IV) and a higher miR-205 serum level showed longer overall survival than those with a lower miR-205 serum concentration (p < 0.01). Furthermore, Cox regression analysis revealed that miR-205 serum levels were independently associated with overall survival. CONCLUSIONS These data indicate that serum miR-205 expression is a novel and valuable biomarker for the diagnosis of glioma and a prognostic factor for those with a tumor at an advanced pathological grade.