Annexin　A2　(ANXA2)　has　been　found　to　be　involved　in　cancer　proliferation,　metastasis　and　prognosis;　however,　its　exact　role　in　nasopharyngeal　carcinoma　(NPC)　radioresistance　remains　unknown.　We　found　that　ANXA2　expression　was　correlated　with　prognosis　in　NPC　patients,　and　longer　overall　survival　in　NPC　patients　with　low　ANXA2　expression　than　those　with　high　ANXA2　expression.　ANXA2　knockdown　increased　the　radiosensitivity　in　radioresistant　NPC　cells,　and　ANXA2　overexpression　decreased　the　radiosensitivity　in　NPC　cells.　Knocking-down　ANXA2　expression　increased　the　irradiation-induced　apoptosis　of　radioresistant　NPC　cells,　and　ANXA2　overexpression　decreased　the　irradiation-induced　apoptosis　of　NPC　cells.　ANXA2　knockdown　induced　G2/M　phase　arrest　in　NPC　cells　post-irradiation,　and　ANXA2　overexpression　abrogated　G2/M　phase　arrest　in　NPC　cells　post-irradiation.　ANXA2　overexpression　resulted　in　inhibition　of　the　p38　MAPK-HSP27　pathway,　while　ANXA2　knockdown　resulted　in　activation　of　the　p38　MAPK-HSP27　pathway.　In　addition,　ANXA2　knockdown　increased　the　radiosensitivity　of　the　xenografted　tumors　in　nude　mice.　Our　data　demonstrate　that　knockdown　of　Annexin　A2　enhanced　radiosensitivity　in　NPC　by　increasing　G2/M-phase　arrest,　apoptosis　and　activating　the　p38　MAPK-HSP27　pathway.　ANXA2　may　be　a　promising　target　used　to　overcome　radioresistance　in　NPC.