Tyrosine phosphorylation of Fas (TNFRSF6/CD95) in its death domain turns off Fas-mediated apoptosis, turns on the pro-survival signal, and has implications in different cancers types. We show here that Fas in its pro-survival state, phosphorylated at Y291 (pY291-Fas), functionally interacts with the epidermal growth factor receptor (EGFR), a key cancer-driving protein and major therapeutic target. Using an evolution-guided pY291-Fas proxy, RNA interference, and site-specific phospho-protein detection, we show that pY291-Fas significantly intensifies EGFR signaling in anti-EGFR-resistant colorectal cancer cells via the Yes-1/STAT3-mediated pathway. The pY291-Fas is essential for the EGF-induced formation of the Fas-mediated nuclear EGFR/STAT3 signaling complex consisting of Fas, EGFR, Yes-1, Src, and STAT3. The pY291-Fas accumulates in the nucleus upon EGF treatment and promotes the nuclear localization of phospho-EGFR and phospho-STAT3, the expression of cyclin D1, the activation of STAT3-mediated Akt and MAPK pathways, and cell proliferation and migration. This novel cancer-promoting function of phosphorylated Fas in the nuclear EGFR signaling constitutes the foundation for developing pro-survival-Fas targeted anti-cancer therapies to overcome disease recurrence in patients with anti-EGFR resistant cancer. Fas (TNFRSF6/CD95), a member of the tumor necrosis factor receptor superfamily, can either induce apopto-sis, which is essential for shutting down chronic immune responses 1-3 and preventing autoimmunity and cancer 4 , or mediate cell survival, proliferation, and motility, which can promote autoimmunity, cancer growth, and metastasis 5-10. With increasing evidence of Fas-mediated pro-survival signaling, the cancer-promoting activities of Fas are now recognized as significant and clinically relevant 11. While inhibiting these activities has shown some clinical promise 12 , the full benefit of this strategy will require a better understanding of the Fas-mediated non-apoptosis signaling. Recently, we have demonstrated that phosphorylation of Fas at tyrosines 232 and 291 (Y232 and Y291) in its intracellular death domain, is a reversible anti-apoptotic/pro-survival multi-signaling switch that determines the outcome of Fas signaling 13. The tyrosine phosphorylation turns off the proapoptotic signal and turns on the pro-survival signals that lead to colorectal cancer cell proliferation and migration induced by its ligand, Fas ligand (FasL/TNFSF6/CD95L). Furthermore, we reported elevated levels of Fas death domain tyrosine phosphorylation, which were a direct molecular indicator of Fas pro-survival signal output, in malignant tissues from some cancer types such as colon, breast, and ovarian cancers 13. These data suggest the probability that the pro-survival signal of Fas may dominantly operate in these cancers. To date, little is known within the complex pro-survival signaling network in cancer regarding the cross-talk between Fas signaling and other cancer-promoting pathways. The epidermal growth factor receptor (EGFR/HER1/ErbB1) is one of the key cancer-driving proteins and an important target of several anti-cancer therapies 14. However, a significant number of patients with KRAS gene mutations do not positively respond to