Abstract Introduction: Recent theoretical [1], pre-clinical [2] and human tumor data [3] suggest anti-hypertensives with an extracellular matrix-depleting effect improve vascular function by reducing the solid stress that can squeeze tumor vessels shut [4]. This work is contrasted by studies showing that certain matrix-depleting anti-hypertensives (angiotensin-II receptor blockers) are also associated with reduced peri-tumoral edema [5]. We here show that combined matrix-depleting and anti-angiogenic therapy does reduce vasogenic edema in newly diagnosed glioblastomas but not in recurrent disease and that the mechanisms of action are therefore not fully understood. Methods: We retrospectively assessed data from 40 patients with newly diagnosed glioblastomas (nGBM) and 30 patients with recurrent glioblastomas (rGBM) receiving cediranib, an oral pan-VEGFR inhibitor, with- (NCT00662506) and without (NCT00305656) chemoradiation, respectively. Conventional, perfusion and vessel caliber MRI were performed at baseline and repeated weekly (nGBM) or monthly (rGBM) [6, 7]. Vasogenic edema was measured as the relative volume of peri-tumoral hyper T2-Fluid Attenuated Inversion Recovery (FLAIR) signal on the conventional MRIs. For nGBM, after cediranib onset, 12/40 patients received angiotensin II receptor blockers (Valsartan), β1 receptor antagonists (Atenolol) or angiotensin-converting enzyme inhibitors (Lisinopril), while 8/40 patients received calcium antagonists (Norvasc, Amlodipine) [3]. Similarly, for rGBM, 15/30 patients received Atenolol and 7/30 patients Norvasc. Results: While angiotensin-system inhibitors (ASIs) significantly improved the perfused vessel fraction (% of tumor values >½ the value of healthy tissue; Wilcoxon P<0.05) and the relative small vessel fraction (<½ the size of healthy tissue; Wilcoxon P<0.01) for both cohorts, reduction of vasogenic edema was only observed in nGBM patients. Here, both cediranib alone and in combination with ASIs reduced the median relative vasogenic edema volume (82% and 54% over study period and compared to baseline values, respectively; Wilcoxon P<0.05), but not for non-ASI calcium antagonists (96%). For rGBMs, cediranib alone reduced the median relative vasogenic edema volume (90%; P<0.05), but not when adding ASIs. Instead, there was a trend towards reduced vasogenic edema with non-ASI calcium antagonists. Conclusion: The potential anti-edema effect associated with ASI anti-hypertensives is an attractive feature for reduced administration of steroids in patients with glioblastoma. However, our data indicate that the matrix-depleting activity of some anti-hypertensives improves vascular function in both nGBMs and rGBMs [3], but only reduces vasogenic edema in the newly diagnosed setting [5]. Further studies to understand the mechanisms of benefit of ASIs in cancer are warranted.