Death receptor Fas/CD95 is a crucial component in the regulation of ligand induced apoptosis in many cell types. It is well known that several cancers exhibit a decreased cell surface expression of Fas and consequently escape the control of Fas-mediated apoptosis, although underlying mechanisms are unclear. PTPN13, a multi-PDZ domain phosphatase, directly interacts with Fas and low surface levels of Fas have been previously correlated with increased levels of PTPN13 in a wide variety of tumour cell lines. Here we report that ENTR-1, an established interacting partner of PTPN13, also regulates cell surface levels of Fas. ENTR-1 forms a novel endocytic complex with PTPN13 that controls Fas-mediated apoptotic signaling by regulating the delivery of internalized Fas receptors from the early endosomes to the endolysosomal degradation pathway. The complex mediates the endosome-to-lysosome sorting of Fas via Dysbindin-Hrs1 axis thereby controlling termination of Fas signal transduction. Taken together, our data provide novel insights into the molecular mechanism of Fas post­endocytic trafficking and signaling. As downregulation of any component of the complex increases Fas receptor levels at the cell surface and affects the sensitivity of the cells to Fas-mediated apoptosis, our findings open possible explanations on how cancer cells regulate cell surface levels of death receptors.