Background: Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers with high mor-tality. Long non-coding RNA heart and neural crest derivatives expressed 2 anti-sense 1 (HAND2-AS1) is down-regulated in several cancers including HCC,yet the precise mechanisms how HAND2-AS1 regulates cell survival in HCC remains poorly understood.Methods: The expression levels of HAND2-AS1 and miR-300 were measured using quantitative real-time PCR. The protein levels of suppressor of cytokine signaling 5 (SOCS5),Bcl-2,Bax and cleaved caspase-3 were determined by Western blot. Cell viability and cell proliferation were assessed using cell counting kit-8 and clone formation assay,respectively. Cell apoptosis was detected using flow cytometry. The inter-actions between HAND2-AS1 and miR-300,miR-300 and SOCS5 were validated using luciferase reporter assay. Results: HAND2-AS1 was down-regulated in HCC tissues and cell lines,and the expression level of HAND2-AS1 was positively correlated to patient survival. HAND2-AS1 over-expression reduced viabil-ity and proliferation in HCC cells. Elevated HAND2-AS1 level induced apoptosis in HCC cells,accompa-nied with increased Bax and cleaved caspase-3 levels and decreased Bcl-2 level. We also validated that HAND2-AS1 acted as a sponge of miR-300,and there was a negative correlation between expression lev-els of HAND2-AS1 and miR-300 in HCC tissues. Furthermore,we found that SOCS5 was a downstream target of miR-300. In addition,miR-300 mimics abolished HAND2-AS1-mediated inhibition of cell viabil-ity and proliferation. miR-300 mimics also reversed the HAND2-AS1-induced apoptosis in HCC cells. Conclusion: lncRNA HAND2-AS1 inhibits proliferation in HCC through regulating miR-300/SOCS5 axis.