Glioblastomas (GBs) are the most aggressive form of primary brain cancer and virtually incurable. Accumulation of regulatory T (T reg) cells in GBs is thought to contribute to the dampening of antitumor immunity. Using a syngeneic mouse model for GB, we tested whether local delivery of cytokines could render the immunosuppressive GB microenvironment conducive to an antitumor immune response. IL-12 but not IL-23 reversed GB-induced immunosuppression and led to tumor clearance. In contrast to models of skin or lung cancer, IL-12-mediated glioma rejection was T cell dependent and elicited potent immunological memory. To translate these findings into a clinically relevant setting, we allowed for GB progression before initiating therapy. Combined intratumoral IL-12 application with systemic blockade of the co-inhibitory receptor CTLA-4 on T cells led to tumor eradication even at advanced disease stages where monotherapy with either IL-12 or CTLA-4 blockade failed. The combination of IL-12 and CTLA-4 blockade acts predominantly on CD4(+) cells, causing a drastic decrease in FoxP3(+) T reg cells and an increase in effector T (T eff) cells. Our data provide compelling preclinical findings warranting swift translation into clinical trials in GB and represent a promising approach to increase response rates of CTLA-4 blockade in solid tumors.