Oncolytic herpes simplex viruses are proving to be effective in clinical trials against a number of cancers. Here, R-115, an oncolytic herpes simplex virus retargeted to human erbB-2, fully virulent in its target cells, and armed with murine interleukin-12 was evaluated in a murine model of glioblastoma. We show that a single R-115 injection in established tumors resulted, in about 30% of animals, in the complete eradication of the tumor, otherwise invariably lethal. The treatment also induced a significant improvement in the overall median survival time of mice and a resistance to recurrence from the same neoplasia. Such a high degree of protection was unprecedented; it was not observed before following treatments with the commonly used, mutated/attenuated oncolytic viruses. This is the first study providing the evidence of benefits offered by a fully virulent, retargeted, and armed herpes simplex virus in the treatment of glioblastoma and paves the way for clinical translation.