We observed that RKIP knockdown increased while RKIP overexpression decreased the phosphorylated level of ERK−1/2 and AKT in the NPC cells and xenograft tumors after irradiation, indicating that RKIP decreases the activation of ERK and AKT signaling in the irradiated NPC cells in vitro and in vivo. This evidence concerns the gene MAPK3 and nasopharyngeal carcinoma.