High-grade gliomas (HGG) are aggressive and highly vascularized brain tumours. Despite multimodality therapy including surgery, radiation therapy and in many cases temozolomide chemotherapy, the prognosis is dismal. Salvage therapies following progression after radiation therapy and chemotherapy have historically yielded disappointing results. Bevacizumab is an interesting antiangiogenic drug used as a second-line treatment but although most patients benefit, essentially all patients ultimately progress. Moreover, some clinical studies have documented low activity of a second attempt at vascular endothelial growth factor pathway inhibition after failure of a first. The use of another drug with a different angiogenic pathway inhibition may probably result in a higher activity. Here, we describe, to our knowledge for the first time, the activity and safety of cilengitide, an agent with a different antiangiogenic and anti-invasive activity, administered in two bevacizumab-refractory patients with HGG. In addition, we present a rapid review of the activity of cilengitide in HGG.