Provided is an application of an EPO/EPOR signal pathway inhibitor or blocker in preparation of drugs for treating hepatocellular carcinoma with polycythemia. The polycythemia caused by the generation of EPO in the hepatocellular carcinoma facilitates the development of the hepatocellular carcinoma, and inhibiting or blocking the EPO/EPOR signal pathway can be used as a new therapeutic target of such hepatocellular carcinoma. Recombinant adenovirus Ad-EPOR-Fc and recombinant protein EPOR-Fc can obviously inhibit the proliferation of cancer cells and decrease the expression level of p-stat3, and have no obvious toxicity to normal liver cells, thereby providing a new idea and method for hepatocellular carcinoma treatment.