Background: Glioblastoma is the most common and aggressive primary brain tumor, with 75-85% of patients historically having recurrence within the original tumor site. We have shown in preclinical studies that inhibition of the SDF1/CXCR4 pathway by the CXCR4 inhibitor Plerixafor increases tumor response to irradiation by inhibition of the recovery of tumor blood vessels. Methods: Newly diagnosed glioblastoma patients were enrolled to the clinical trial using the investigational agent Plerixafor after standard radiation therapy and temozolomide (NCT01977677). To date, 28 patients out of the planned accrual of 29 have been enrolled to this study. Normalized relative cerebral blood volume (rCBV) ratios were calculated by the mean rCBV within the 95% isodose radiation field one month post-radiation as compared to contralateral white matter outside of the radiation field. Our imaging analysis compares patients treated with Plerixafor compared to a control group receiving standard therapy (chemo-RT). Results: There was a significant reduction in rCBV measured by DSC-MRI within the 95% isodose field one month after radiation therapy in patients receiving Plerixafor compared to control (p < 0.02). The rCBV out of the radiation field was similar between patients receiving Plerixafor compared to control patients one-month post radiation therapy. As of February 7, 2017, only 2 of the total of 9 recurrences occurred within the irradiated field. The rate of out of field recurrence (77%) was therefore much higher than expected (20%), with statistical significance (p < 0.03, Fisher’s exact test). Conclusions: We show that Plerixafor has a meaningful impact on local control of glioblastoma. Furthermore, DSC-MRI could be a useful biomarker of its efficacy.