Cyclophosphamide treatment on a medium-dose, intermittent chemotherapy (MEDIC) schedule activates both innate and adaptive immunity leading to major regression of implanted gliomas. Here, we show that this MEDIC treatment regimen induces tumor cell autonomous type-I interferon signaling, followed by release of soluble factors that activate interferon-stimulated genes in both tumor cells and tumor-infiltrating immune cells. In cultured GL261 and CT-2A glioma cells, activated cyclophosphamide stimulated production and release of type-I interferons, leading to robust activation of downstream gene targets. Antibody against the type-I interferon receptor IFNAR1 blocked the cyclophosphamide-stimulated induction of these genes in both cultured glioma cells and implanted gliomas. Furthermore, IFNAR1 antibody strongly inhibited the MEDIC cyclophosphamide-stimulated increases in tumor cell infiltration of macrophages, dendritic cells, B-cells, as well as natural killer cells and cytotoxic T-cells and their cytotoxic effectors. Finally, cyclophosphamide-treated dying glioma cells producing type-I interferons were an effective vaccine against drug-naïve glioma cells implanted in vivo. Thus, cyclophosphamide induces local, tumor cell-centric increases in type-I interferon signaling, which activates immunogenic cell death and is essential for the striking antitumor immune responses that MEDIC cyclophosphamide treatment elicits in these glioma models.