The regulation of the necrotic death and its relevance in anticancer therapy are largely unknown. Here, we have investigated the proapoptotic and pronecrotic activities of two ubiquitin-proteasome system inhibitors: bortezomib and G5. The present study points out that the glioblastoma cell lines U87MG and T98G are useful models to study the susceptibility to apoptosis and necrosis in response to ubiquitin-proteasome system inhibitors. U87MG cells show resistance to apoptosis induced by bortezomib and G5, but they are more susceptible to necrosis induced by G5. Conversely, T98G cells are more susceptible to apoptosis induced by both inhibitors but show some resistance to G5-induced necrosis. No overt differences in the induction of Noxa and Mcl-1 or in the expression levels of other components of the apoptotic machinery were observed between U87MG and T98G cells. Instead, by comparing the transcriptional profiles of the two cell lines, we have found that the resistance to G5-induced necrosis could arise from differences in glutathione synthesis/utilization and in the microenvironment. In particular, collagen IV, which is highly expressed in T98G cells, and fibronectin, whose adhesive function is counteracted by tenascin-C in U87MG cells, can restrain the necrotic response to G5. Collectively, our results provide an initial characterization of the molecular signals governing cell death by necrosis in glioblastoma cell lines.