Recently, there has been greater awareness that combination radiation and temozolomide used to treat glioblastomas may cause increased contrast enhancement on the first post radiation MRI scan. However, this increased enhancement may stabilize or decrease over time and represent pseudo-progression (psPD) rather than true progressive disease. It has never been shown that this phenomenon is greater with combination therapy than radiation alone. To address this question, we reviewed MRI scans in glioblastoma patients treated with radiation alone versus patients treated with radiation and concomitant temozolomide and compared the frequency of psPD in the two groups. Eighteen of 47 patients (38%) treated with radiation alone demonstrated enlargement on their first post-radiation MRI scan and 11 of these 18 (61%) proved to have psPD as defined by no further enlargement on stable therapy for 3 months following radiation. Twenty-four of 45 patients (53%) treated with radiation and temozolomide had enlargement on their first post-radiation MRI scan and 13 of these 24 (54%) had psPD. Median overall survival (OS) in patients with psPD treated with radiation alone was 15.6 versus 12.8 months in those without psPD. Median OS in patients treated with radiation and concomitant temozolomide who had psPD was 24.4 versus 15.9 months in those who did not have psPD. We were unable to detect a difference in OS between the four groups. Presence of psPD, independent of treatment, was associated with prolonged progression-free survival (P = 0.05) but not OS. psPD may be more common in combination therapy but most likely by a small margin.