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Henry M Smilowitz,1 Alexandria Meyers,1 Khalil Rahman,1 Nathaniel A Dyment,2 Dan Sasso,1 Crystal Xue,3 Douglas L Oliver,4 Alexander Lichtler,5 Xiaomeng Deng,6 Sharif M Ridwan,1 Lauren J Tarmu,7,8 Qian Wu,9 Andrew L Salner,10 Ketan R Bulsara,11 Daniel N Slatkin,12 James F Hainfeld12 1Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, 2Department of Orthopedic Surgery, University of Pennsylvania, Philadelphia, PA, 3George Washington University School of Medicine, Washington, DC, 4Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, 5Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT, 6David Geffen School of Medicine at UCLA, Student Affairs Office, Los Angeles, CA, 7Department of Human Behavior, College of Southern Nevada, 8Department of Anthropology, University of Nevada, Las Vegas, NV, 9Department of Anatomic Pathology, University of Connecticut Health Center, Farmington, 10The Gray Cancer Center, Hartford Hospital, Hartford, 11Division of Neurosurgery, UConn Health, Farmington, CT, 12Nanoprobes, Inc, Yaphank, NY, USA Background: Intravenously (IV)-injected gold nanoparticles (AuNPs) powerfully enhance the efficacy of X-ray therapy of tumors including advanced gliomas. However, pharmacokinetic issues, such as slow tissue clearance and skin discoloration, may impede clinical translation. The direct infusion of AuNPs into the tumor might be an alternative mode of delivery. Materials and methods: Using the advanced, invasive, and difficult-to-treat F98 rat glioma model, we have studied the biodistribution of the AuNPs in the tumor and surrounding brain after either IV injection or direct intratumoral infusion by convection-enhanced delivery using light microscopy immunofluorescence and direct gold visualization. Results: IV-injected AuNPs localize more specifically to intracerebral tumor cells, both in the main tumor mass and in the migrated tumor cells as well as the tumor edema, than do the directly infused AuNPs. Although some of the directly infused AuNPs do access the main tumor region, such access is largely restricted. Conclusion: These data suggest that IV-injected AuNPs are likely to have a greater therapeutic benefit when combined with radiation therapy than after the direct infusion of AuNPs. Keywords: gold nanoparticles, glioma, edema, IV injection, convection-enhanced delivery, fluorescence microscopy, gold enhance