Background:　Nucleolar　protein　6　(NOL6)　is　a　nucleolar　RNA-associated　protein　that　is　highly　conserved　between　species.　It　has　been　proved　to　be　associated　with　the　prognosis　of　liver　cancer.　However,　the　underlying　mechanism　has　not　been　fully　established.　This　study　aimed　to　assess　the　relationship　between　NOL6　and　liver　cancer　prognosis.　Methods:　We　constructed　an　NOL6-short　hairpin　RNA　(shRNA)-expressing　lentivirus.　Through　viral　transfection,　cell　growth　assay　and　fluorescence-activated　cell　sorting,　we　evaluated　the　effect　of　shRNA-mediated　NOL6　knockdown　on　the　proliferation,　colony　formation,　and　apoptosis　of　hepatocellular　carcinoma　(HCC)　cells.　The　relationship　between　NOL6　expression　and　HCC　patient　survival　has　been　established　through　bioinformatics　analysis.　We　also　explored　the　downstream　molecular　regulatory　network　of　NOL6　in　HCC　by　performing　an　Ingenuity　Pathway　Analysis　in　the　database.　Results:　Increased　NOL6　expression　was　detected　in　HCC　cells　compared　to　normal　controls;　HCC　patients　with　high　NOL6　expression　had　poorer　prognoses　than　those　with　low　expression.　NOL6　knockdown　inhibited　HCC　cell　proliferation,　apoptosis,　and　colony　formation.　Also,　MAPK8,　CEBPA,　and　FOSL1　were　selected　as　potential　downstream　genes　of　NOL6.　Conclusions:　NOL6　up-regulates　HCC　cell　proliferation　and　affects　downstream　expression　of　related　genes.　Moreover,　NOL6　is　considered　to　be　associated　with　poor　prognosis　in　HCC　patients.