The exact mechanisms of gender disparity in hepatocellular carcinoma (HCC) are largely unknown.Reanalysis of large-scale genomic profiles lead us to explore the gender differences from copy number variations (CNVs).UBE2D1, one of genes harbored in the gender associated CNVs, can facilitate the HCC growth by activating the p53 ubiquitination through MDM2.Additionally, the gender disparity of CNVs in HCC was ascribed to the continuous IL-6 microenvironment.Continuous IL-6 stimulation promoted the replication stress response and genomic instability to drive the genomic amplification of UBE2D1 by activating STAT3 and thus repressing RAD51B.Our findings clarified the mechanisms of gender disparity in CNVs and suggested UBE2D1 and RAD51B as potential therapeutic targets for HCC.