Hepatocellular carcinoma has been identified as the fifth most common cancer in men and the ninth in women worldwide. Despite many efforts have been made in recent years, the overall survival rate of patients with hepatocellular carcinoma still remain unsatisfied. Therefore, exploring the mechanisms underlying the progression of hepatocellular carcinoma is essential for developing novel treatments to improve patient prognosis. HOXA11-AS, transcribed from the opposite strand of the protein-coding gene HOXA11, has been identified to be associated with the malignant characteristics of several cancers. However, the biological role and molecular mechanism of HOXA11-AS in hepatocellular carcinoma still need to be further investigated. In the current study, the expression of HOXA11-AS in the hepatocellular carcinoma cell lines and tissues was measured by quantitative real-time PCR. Loss-of-function and gain-of-function approaches were applied to investigate the proliferative function of HOXA11-AS in hepatocellular carcinoma cells. Results from flow cytometric analysis of apoptosis and cell cycle distribution revealed that HOXA11-AS promoted hepatocellular carcinoma cells proliferation through regulating cell cycle and apoptosis. Gene chip technology and quantitative real-time PCR confirmed that DUSP5 was a downstream target of HOXA11-AS. RNA immune co-precipitation assays, RNA pull-down and Chromatin immunoprecipitation assays confirmed that HOXA11-AS could recruit EZH2 to the promoter region of DUSP5, which therefore suppressed the transcription of DUSP5. Collectively, these findings revealed that HOXA11-AS functions as an oncogene in hepatocellular carcinoma through interacting with polycomb-repressive complex2.