In summary, our data demonstrate that: i) RKIP was downregulated in NPC cells and tissues with high metastatic potentials, and low RKIP expression was an independent predictor for poor overall survival of NPC patients; ii) RKIP downregulation promoted NPC cell invasion, metastasis and EMT-like molecular alterations both in vitro and in vivo; iii) RKIP inhibited Stat3 activation in NPC cells by interacting with and then blocking Stat3 phosphorylation in NPC cells; iv) RKIP downregulation promoted NPC invasion, metastasis and EMT-like molecular alterations by activating Stat3 signaling. The gene discussed is PEBP1; the disease is nasopharyngeal carcinoma.