The lack of serum biomarkers for assessing the prognosis of patients with cerebral glioblastoma multiforme (GBM) prompted the present study in order to evaluate the significance of serum YKL-40 values in patients operated on for glioblastoma. An homogeneous population of 60 patients who underwent surgical removal of GBM underwent a standard treatment (surgery, radiotherapy, chemotherapy in the same schedule) and standard radiological monitoring (same MRI sequences at pre-defined stages). Serum YKL-40 levels (Quidel Corporation, San Diego, CA) were evaluated after dividing patients into two groups on the basis of the extent of resection (total or sub-total) according to the MRI results obtained within 48 h following surgery. YKL-40 serum values, significantly higher in GBM patients than in healthy subjects, were also higher among patients who had undergone subtotal resection than in patients who underwent extensive resection. The effect of YKL-40 on overall survival was analyzed by comparing the change in marker concentration occurring in the first postoperative week with the baseline value. A significant (P = 0.04) hazards ratio of 1.97 was found at multivariate analysis. A significant association with shorter outcome (median survival time, 76 days) was found in patients whose postoperative YKL-40 concentration increases higher than, or equal to, 100%; a 50% increase can still be considered a negative prognostic index. The evaluation of the biochemical marker YKL-40 might provide earlier and additional information to that obtained using traditional factors and be a further aid in establishing the prognosis of GBM patients who have undergone surgery.