Patients with high-grade glioma are at elevated risk of venous thromboembolism (VTE). The relationship between VTE and survival in glioma patients remains unclear, as does the optimal protocol for chemoprophylaxis. The purpose of this study was to assessthe incidence of and risk factors associated with VTE in patients with high-grade glioma, and the correlation between VTE and survival in this population. Furthermore, we sought to define a protocol for perioperative DVT prophylaxis. This was a retrospective review of patients who underwent craniotomy for resection of high-grade glioma (WHO grade III or IV) at Northwestern University between 1999 and 2010. A total of 336 patients met inclusion criteria. 53 patients developed postoperative VTE (15.7 %). Median survival was 12.0 months and was not significantly different between VTE(+) and VTE(-) patients. Demographics and surgical factors were not significantly correlated with VTE development. Prior history of VTE was highly predictive of postoperative VTE (OR 7.1, p < .01), as was seizure (OR 2.4, p = .005). Increased duration of postoperative ICU stay was also a risk factor for VTE (p = .025). 25 patients in our study received prophylactic anticoagulation(pAC) with either heparin or enoxaparin. Early initiation of pAC was associated with decreased incidence of VTE (p = .042). There were no hemorrhagic complications in patients receiving pAC. VTE is a common complication in high-grade glioma patients. Early initiation of anticoagulation is safe and may decrease the risk of VTE. We recommend initiation of chemoprophylaxis on postoperative day 1 in patients without contraindication.