Deletion of type I IFN genes and resistance to apoptosis induced by type I IFNs are common in glioblastoma. Here we have investigated the importance of the constitutive weak IFN-signaling in the apoptotic response to IFN-α in glioblastoma cells. U87MG cells hold a deletion of type I IFN genes, whereas in T98G cells the spontaneous IFN signaling is intact. In response to IFN-α U87MG cells produce much less TRAIL, while other IFN-inducible genes were efficiently up-regulated. Alterations in TRAIL promoter sequence and activity were not observed. DNA methylation can influence TRAIL transcription but without overt differences between the two cell lines. We also discovered that TRAIL mRNA stability is influenced by IFN-α, but again no differences can be appreciated between the two cell lines. By silencing IFNAR1 we provide evidences that the spontaneous IFN signaling loop is required to sustain elevated levels of TRAIL expression, possibly through the regulation of IRF-1. Despite the presence/absence of the constitutive IFN signaling, both cell lines were resistant to IFN-α induced apoptosis. Targeting the deisgylase USP18 can overcome resistance to IFN-induced apoptosis only in T98G cells. Alterations in elements of the extrinsic apoptotic pathway, such as Bid and c-FLIP contribute to apoptotic resistance of U87MG cells. Down-regulation of USP18 expression together with the induction of ER-stress efficiently restored apoptosis in U87MG cells. Finally, we demonstrated that the BH3-only protein Noxa provides an important contribution in the apoptotic response to ER-stress in USP18 silenced cells.