Background: Glioblastoma (GB) is the most malignant primary brain tumor. Isolated restricted diffusion (IRD) is restricted diffusion outside the confines of enhancing tumor with no corresponding enhancement on post contrast study. The aim of our study was to prospectively assess the incidence of IRD in GB patients, determine how often these foci proceed to contrast enhancement on follow up, and analyze the survival pattern. Methods: In a prospective pilot cohort study, consecutive adult patients with GB on initial MRI of brain, were included and screened for IRD. All images were independently analyzed by two experienced radiologists. The survival pattern of patients with IRD was assessed with Cox-regression and Kaplan-Meier curve analysis. Results: Of the 52 patients (median age- 63 years; male-63.5%), 21% (11 of 52) exhibited IRD. Inter-rater agreement on the diagnosis of IRD foci was fair (kappa=0.29). Seven (64%) showed enhancement in the IRD focus. The Kaplan Meier analysis revealed a significant decrease (p=0.035) in the survival was observed among patients with IRD focus. Conclusions: IRD focus was seen in 21% of patients with GB, with 64% of these demonstrating enhancement at the IRD focus on follow up imaging. A shorter survival was associated with IRD foci.