The purpose of this study was to evaluate diffusion parameters at pre-, mid-, and post-radiation therapy (RT) in contrast-enhancing and nonenhancing lesions of postsurgical glioblastoma multiforme patients treated with the standard of care RT concurrently with temozolomide (TMZ) followed by adjuvant TMZ and an antiangiogenic drug. The diffusion parameters explored include baseline and short-term changes in apparent diffusion coefficient, fractional anisotropy, and eigenvalues. These diffusion parameters were examined as early markers for disease progression by relating them to clinical outcome of 6-month progression-free survival. The results indicated that changes from mid- to post-RT were significantly different between patients who progressed within 6 months vs those who were free of progression for 6 months after initiation of therapy. The study also showed that the changes in diffusion parameters from the mid- to post-RT scan may be more significant than those from pre- to mid-RT and pre- to post-RT. This is important because the mid-RT scan is currently not performed as part of the standard clinical care.