[Abstract] Objective: To explore the role of adhesion molecule with Ig like domain 2 (AMIGO2) in the proliferation of nasopharyn‐ geal carcinoma (NPC) cells and its mechanisms. Methods: A total of 10 NPC tissue samples and 10 normal nasopharyngeal epithelial tissue samples collected at Fujian Cancer Hospital during September 2017 and November 2017 were used for this study; in addition, NPC cell lines (CNE-1, CNE-2, SUNE-1, 6-10B, C666-1) and human immobilized nasopharyngeal epithelial cell line NP69 were also collected. The relative expression of AMIGO2 mRNAin above mentioned tissues and cell lines was detected by qPCR. Lentivirus vectors were constructed to interfere AMIGO2 mRNA expression, and qPCR was used to verify its interference efficiency. CCK-8 method, Clonal formation and Flow cytometry were performed to evaluate the effect of AMIGO2 interference on proliferation, clone formation and apoptosis of NPC cells. The influence of AMIGO2 interference on PI3K/AKT/mTOR signaling pathway and proliferation related molecular markers in NPC cells was assessed by Western blotting. Results: The results of qPCR showed that AMIGO2 was highly expressed in NPC tissues, CNE-2, and SUNE-1 cells (all P<0.01). The interference efficiency of AMIGO2 in CNE-2 and SUNE-1 cells could reach over 50%. The interfering of AMIGO2 expression significantly inhibited the proliferation and clone formation of CNE-2 and SUNE-1 cells (all P<0.01), promoted cell apoptosis (all P<0.01), reduced the phosphorylated protein expression levels of PI3K, AKT and mTOR in SUNE-1 cells (all P<0.01), as well as down-regulated the protein expressions of survivin and PCNA (all P<0.01). Conclusion: AMIGO2 may promote the proliferation as well as inhibit apoptosis of NPC cells by activating the PI3K/AKT/mTOR signaling pathway, suggesting that AMIGO2 may be a potential target for NPC therapy.