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Anaplastic thyroid carcinoma (ATC) are resistant to standard therapies and has no effective treatment. Eukaryotic translation initiation factor 5A2 (EIF5A2) has shown to be upregulated inmany malignant tumors and proposed to be a critical gene involved in tumor metastasis. In thisstudy, we aim to investigate the expression status of EIF5A2 in human ATC tissues, and to study therole and mechanisms of EIF5A2 in ATC tumorigenesis in vitro and in vivo. Expression of EIF5A2protein were analyzed in paraffin-embedded human ATC tissues and adjacent nontumorous tissues(ANCT) (n=24) by immunochemistry. Expression of EIF5A2 mRNA and protein were analyzed infresh-matched ATC and ANCT (n=23) and ATC cell lines by real-time PCR and western blotting. Theeffect of targeting EIF5A2 with short hairpin RNA (shRNA) or EIF5A2 overexpression on the ATCtumorigenesis and TGF-β/Smad2/3 signals in vitro and in vivo was investigated. Expression ofEIF5A2 was significantly upregulated in ATC tissues and cell lines compared with ANCT and normalfollicular epithelial cell line. Functional studies found that targeting EIF5A2 induced SW1736 celldeath in vitro and in vivo, followed by significantly downregulated phosphorylation of Smad2/3(p-Smad2/3) in SW1736 cells at the protein level. Ectopic expression of EIF5A2 could promoted8505C cell growth in vitro and in vivo, followed by significantly upregulated p-Smad3 at the proteinlevel. Recombinant human TGF-β1 (hTGF-β1) treatment decreased the anti-proliferative activity ofthe EIF5A2 downexpressing 8505C cells through reversing p-Smad2/3. Using the specific inhibitorSB431542 to block TGF-β pathway or Smad3 siRNA to knockdown of Smad3 increased theanti-proliferative activity of the EIF5A2 overexpressing 8505C cells through inhibiting p-Smad2/3.Our findings indicated that EIF5A2 controled cell growth in ATC cells, and EIF5A/TGF-β/Smad2/3signal may be as a potential therapeutic target for ATC treatment.