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Docosahexaenoic acid (DHA) induces apoptotic cell death through several mechanisms in cancer cells. We have previously demonstrated that DHA triggers apoptosis by increasing reactive oxygen species (ROS) accumulation and the ROS-mediated apoptosis caused by DHA is associated with Nrf2 signaling activation. Here we report that DHA-induced cell death is more susceptible through upregulation of p62-Nrf2 and downregulation of p-eIF2α in LMP-1-expressing nasopharygeal carcinoma (NPC) cells. Treatment of four human NPC cells (CNE, CNE-LMP1, HONE, HONE-EBV) with DHA for 24 hr resulted in a dose-dependent inhibition of cell growth. The DHA effect was due to the induction of apoptosis, given that DHA increased the cleaved form of PARP as well as the number of TUNEL-positive cells. The inhibition of CNE-LMP1 and HONE-EBV cells after DHA treatment is more susceptible compared with CNE and HONE cells without LMP1 by MTT assay. The level of p62 and Nrf2 of LMP1-NPC cells were increased after DHA pretreatment compared to control NPC cells. On the other hand, the level of p-eIF2α produced reverse result. The activation of Nrf2 signal seems to result from decreased Nrf2 inhibitor, Keap1, because DHA remarkably attenuated Keap1 expression levels. Moreover, silencing Nrf2 by small interfering RNAs inhibited the cytotoxic effect of DHA, indicating that Nrf2 activation plays a positive role in the process of DHA-induced apoptosis. Increased staining for LMP1 and p62 was observed in NPC tissues when compared with the nonneplastic (chronic inflammation) tissues. These results suggest that differential regulation of p62/p-eIF2α/NRF2 contributes to susceptible cell death by DHA in LMP-1-expressing NPC cells. Thus, utilization of DHA may represent a promising therapeutic approach for chemoprevention and treatment of human NPC. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2015R1D1A1A01056887) and by the framework of international cooperation program managed by National Research Foundation of Korea (2015K2A2A6002008)]. Citation Format: Kaipeng Jing, Soyeon Shin, Seung-Hyeon Han, Tong Wu, Kyu Lim. Upregulation of p62/Nrf2 and downregulation of p-eIF2a provide more susceptible to docosahexaenoic acid-induced cell death in LMP-1 expressing nasopnaryngeal carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1868.