Although overexpression of eukaryotic translation initiation factor 4E (eIF4E) is associated with enhanced growth and poor prognosis in nasopharyngeal carcinoma (NPC), the function of eIF4E in NPC response to chemotherapy has not been revealed. In this work, we demonstrate that eIF4E inhibition using both ribavirin and siRNA targets NPC cells and enhances the efficacy of 5-fluorouracil (5-FU). Mechanism studies indicate that 5-FU treatment increases phosphorylation of eIF4E in NPC cells, and this is dependent on ERK activation. eIF4E inhibition thus significantly sensitizes NPC cell response to 5-FU. Of note, ribavirin is a clinically available anti-viral drug. We show that ribavirin exhibits preferential toxicity to NPC with normal nasopharyngeal epithelial cells largely unaffected. Ribavirin acts on NPC cells via inhibiting eIF4E/Akt signaling, and the suppression of eIF4E by ribavirin are not the consequence of inhibition of eIF4E upstream signaling: Mnk and mTOR. In two independent NPC xenograft mouse models, ribavirin at well-tolerated dose that significantly inhibited NPC growth as single drug alone and its combination with 5-FU completely arrests tumor growth throughout the whole duration of treatment, without causing toxicity in mice. Our findings provide the better understanding on the role of eIF4E in NPC in response to 5-FU and preclinical rationale to explore ribavirin as a sensitizing strategy to treat NPC, particularly in those who develop 5-FU resistance.