The peroxisome proliferator-activated receptor γ coactivator (PGC)-1α is a master regulator of mitochondrial biogenesis and controls metabolism by coordinating transcriptional events. Here， we interrogated whether PGC-1α is involved in tumor growth and the metabolic flexibility of glioblastoma cells. PGC-1α was expressed in a subset of established glioma cell lines and primary glioblastoma cell cultures. Furthermore， a higher PGC-1α expression was associated with an adverse outcome in the TCGA glioblastoma dataset. Suppression of PGC-1α expression by shRNA in the PGC-1α-positive U343MG glioblastoma line suppressed mitochondrial gene expression， reduced mitochondrial membrane potential， and diminished oxygen as well as glucose consumption， and lactate production. Compatible with the known PGC-1α functions in reactive oxygen species (ROS) metabolism， glioblastoma cells deficient in PGC-1α displayed ROS accumulation， had reduced RNA levels of proteins involved in ROS detoxification， and were more susceptible to death induction by HO compared with control cells. PGC-1αsh cells also had impaired proliferation and migration rates and displayed less stem cell characteristics. Complementary effects were observed in PGC-1α-low LNT-229 cells engineered to overexpress PGC-1α. In an xenograft experiment， tumors formed by U343MG PGC-1αsh glioblastoma cells grew much slower than control tumors and were less invasive. Interestingly， the PGC-1α knockdown conferred protection against hypoxia-induced cell death， probably as a result of less active anabolic pathways， and this effect was associated with reduced epidermal growth factor expression and mammalian target of rapamycin signaling. In summary， PGC-1α modifies the neoplastic phenotype of glioblastoma cells toward more aggressive behavior and therefore makes PGC-1α a potential target for anti-glioblastoma therapies.