Recurrent high-grade gliomas are resistant to chemotherapy and have poor prognosis. The combination of irinotecan and bevacizumab has been reported to be an active regimen in the treatment of this disease. Herein we report our experience with this regimen with the objective of evaluating its efficacy and examining its safety profile. We performed a retrospective review of 27 patients with recurrent or progressive high-grade gliomas treated at the Cleveland Clinic Brain Tumor and Neuro-Oncology Center from 7/2005 through 10/2006. Patients with at least one prior chemotherapy regimen were included. Patients with prior irinotecan or bevacizumab were excluded. Outcomes were analyzed on an intention-to-treat basis and estimated by the Kaplan-Meier method. The median age of the group was 46 years and the median number of prior therapies was two. Eighteen of 27 patients have progressed, and 11 patients have died at time of analysis. Progression-free survival at 6 months is 46% and overall survival at 6 months is 84% with a median overall survival of 12.6 months. Of 12 patients with pretreatment radiographic evidence of intracranial hemorrhage, only one developed symptomatic progression of hemorrhage that required termination of therapy. Our experience suggests that the combination of irinotecan and bevacizumab improves the outcome in progressive high-grade gliomas when compared to historical results. While the rate of severe toxicities is consistent with prior reports and mandates careful selection of patients, asymptomatic, stable intracranial blood products or hemorrhage is likely not an absolute contraindication to therapy.