Our objective is to assess treatment efficacy, safety and pattern of response and recurrence in patients with recurrent high-grade glioma treated with bevacizumab and irinotecan. We reviewed retrospectively 51 patients with recurrent high-grade glioma treated with this combination at the Henry Ford Hermelin Brain Tumor Center from 11/15/2005 to 04/01/2008. The 6-month progression-free survival (PFS) for anaplastic gliomas (AGs) was 78.6 and 63.7% for glioblastoma. The median PFS was 13.4 months for AG and 7.6 months for those with glioblastoma. The overall survival rate (OS) at 6 months was 85.7% for AG and 78.0% for glioblastoma. The 12-month OS was 77.9% for AG and 42.6% for glioblastoma. The median OS time for AGs was not reached and was 11.5 months for those with glioblastoma. Thirty-six out of 51 (70.59%) patients demonstrated partial (32/51) or complete (4/51) radiographic response to treatment and 8/51 (15.69%) remained stable. Of the 38 who demonstrated progression on post-gadolinium studies, 23 showed distant progression with or without local recurrence. Seven patients showed progression on FLAIR without concordant findings on post-Gd sequences. Six patients (11.76%) discontinued treatment due to a treatment-emergent adverse event, including one with end-stage renal failure and another with gastric perforation. No symptomatic intracranial hemorrhages were reported. Patients with recurrent high-grade glioma treated with bevacizumab plus irinotecan demonstrate an excellent radiographic response rate and improved clinical outcome when compared to historical data. The high rate of distant tumor progression suggests that tumors may adapt to inhibition of angiogenesis by increased infiltration and vascular co-option.