Abstract Background Treatment of newly diagnosed GBM with postoperative RT and concomitant TMZ followed by 6 months of TMZ maintenance therapy has been shown to significantly improve overall survival compared with RT alone. Standard clinical assessments of these patients include Gd-MRI as well as neurologic evaluation. Frequently, patients exhibit immediate post-RT changes in enhancement on Gd-MRI that mimic tumor progression (ie, pseudoprogression or radiation-induced imaging changes). With the introduction of concomitant RT plus TMZ for treatment of malignant glioma, there appears to be an increasing incidence of pseudoprogression. Case Description In our experience, pseudoprogression after concomitant RT plus TMZ is typically not observed at first imaging immediately after completion of the therapy; but delayed focal enhancement mimicking tumor progression frequently occurs during the 6 months of maintenance therapy with TMZ. Pseudoprogression may reflect the radiosensitizing effect of TMZ during concomitant therapy, and retaining patients on treatment allows them to have enhanced survival and preserved quality of life. We observed 3 cases of pseudoprogression among 54 consecutive patients who were treated with this regimen. These patients developed pseudoprogression within 2 to 6 months after completion of concomitant RT plus TMZ, but all 3 patients completed maintenance chemotherapy and remained progression free for at least 15 months after diagnosis. Conclusion Functional imaging may improve the noninvasive diagnosis of pseudoprogression, but randomized prospective studies are needed to evaluate the real impact of pseudoprogression and validate neuroradiological techniques able to make a reliable distinction between tumor recurrence and pseudoprogression.