Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward T_H2 cytokine production are long-recognized T-cell defects in these patients whose etiology has remained elusive for >30 years. We show here that absolute counts of both CD4⁺ T cells and CD4⁺CD25⁺FOXP3⁺CD45RO⁺ T cells (T_regs) are greatly diminished in patients with malignant glioma, but T_regs frequently represent an increased fraction of the remaining CD4 compartment. This increased T_reg fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, T_reg removal eradicates T-cell proliferative defects and reverses T_H2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, T_reg depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for T_regs in facilitating tumor immune evasion in the central nervous system. (Cancer Res 2006; 66(6): 3294-302)