OBJECTIVES: Glucose metabolism outside of oxidative phosphorylation, or aerobic glycolysis (AG), is a hallmark of active cancer cells that is not directly measured with standard (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In this study, we characterized tumor regions with elevated AG defined based on PET measurements of glucose and oxygen metabolism. METHODS: Fourteen individuals with high-grade brain tumors underwent structural MR scans and PET measurements of cerebral blood flow (CBF), oxygen (CMRO2) and glucose (CMRGlu) metabolism, and AG, using (15)O-labeled CO, O2 and H2O, and FDG, and were compared to a normative cohort of 20 age-matched individuals. RESULTS: Elevated AG was observed in most high-grade brain tumors and it was associated with decreased CMRO2 and CBF, but not with significant changes in CMRGlu. Elevated AG was a dramatic and early sign of tumor growth associated with decreased survival. AG changes associated with tumor growth were differentiated from the effects of nonneoplastic processes such as epileptic seizures. CONCLUSIONS: Our findings demonstrate that high-grade brain tumors exhibit elevated AG as a marker of tumor growth and aggressiveness. AG may detect areas of active tumor growth that are not evident on conventional FDG PET.