To the best of our knowledge, this is the first study to show that (i) Ubenimex can reverse MDR of HCC cells; (ii) Pim-3 expression is positively associated with drug resistance and can be induced by CD13 in HCC cells; (iii) Ubenimex down-regulates Pim-3 expression by targeting CD13 to reverse MDR of HCC cells; (iv) Promotion of Cisplatin-induced apoptosis and inhibition of MRP expression occurs upon down-regulation of Pim-3 by Ubenimex. This evidence concerns the gene ANPEP and hepatocellular carcinoma.