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Aim: To evaluate the in vivo antitumor effects of antisense oligonucleotides tar-geting midkine (MK-AS). Methods: An in situ human hepatocellular carcinoma (HCC) model was established in mice livers orthotopically. The MK-AS and 5-fluorouracil (5-Fu) were administered intravenously. The tumor sizes and plasma alpha-fetoprotein (AFP) were measured by calipers and radiation immunoassay respectively. The morphology of tumors was evaluated by hematoxylin-eosin staining of histological sections. Human MK, p53, Bax, Bcl-2, and caspase-3 protein content were detected by Weste blotting. Results: MK-AS signifi- candy inhibited in situ human HCC growth in mice compared with the saline group in a dose-dependent manner. After the treatment with MK-AS or with 5-Fu, the plasma AFP concentration decreased in a dose-dependent manner. Interestingly,MK-AS also clearly downregulated the protein level of Bcl-2, and upregulated p53, Bax, and caspase-3 in the hepatocellular carcinoma tissue. Conclusion: These results demonstrated that MK-AS was an effective antitumor antisense oligo-nucleotide in vivo in mice; its antitumor effect is associated with the increase of pro-apoptotic proteins, such as p53, Bax, and caspase-3, and the decrease of the anti-apoptotic protein, Bcl-2.