Temozolomide is the most widely used chemotherapy for patients with glioblastoma (GBM) despite the fact that approximately half of treated patients have temozolomide resistance and all patients eventually fail therapy. Due to the limited efficacy of existing therapies, immunotherapy is being widely investigated for patients with GBM. However, initial immunotherapy trials in GBM patients have had disappointing results as monotherapy. Therefore, combinatorial treatment strategies are being investigated. Temozolomide has several effects on the immune system that are dependent on mode of delivery and the dosing strategy, which may have unpredicted effects on immunotherapy. Here we summarize the immune modulating role of temozolomide alone and in combination with immunotherapies such as dendritic cell vaccines, T-cell therapy, and immune checkpoint inhibitors for patients with GBM.