Objective:　Neoantigens　derived　from　tumor-specific　genomic　alterations　have　demonstrated　great　potential　for　immunotherapeutic　interventions　in　cancers.　However,　the　comprehensive　profile　of　hepatocellular　carcinoma　(HCC)　neoantigens　and　their　complex　interplay　with　immune　microenvironment　and　tumor　evolution　have　not　been　fully　addressed.　Methods:　Here　we　integrated　whole　exome　sequencing　data,　transcriptome　sequencing　data　and　clinical　information　of　72　primary　HCC　patients　to　characterize　the　HCC　neoantigen　profile,　and　systematically　explored　its　interactions　with　tumor　clonal　evolution,　driver　mutations　and　immune　microenvironments.　Results:　We　observed　that　higher　somatic　mutation/neoantigen　load　was　associated　with　better　clinical　outcomes　and　HCC　patients　could　be　further　divided　into　two　subgroups　with　distinct　prognosis　based　on　their　neoantigen　expression　patterns.　HCC　subgroup　with　neoantigen　expression　probability　high　(NEP-H)　showed　more　aggressive　pathologic　features　including　increased　incidence　of　tumor　thrombus　(P=0.038),　higher　recurrence　rate　(P=0.029),　more　inclined　to　lack　tumor　capsule　(P=0.026)　and　with　more　microsatellite　instability　sites　(P=0.006).　In　addition,　NEP-H　subgroup　was　also　characterized　by　higher　chance　to　be　involved　in　tumor　clonal　evolution　[odds　ratio　(OR)=46.7,　P＜0.001].　Gene　set　enrichment　analysis　revealed　that　upregulation　of　MYC　and　its　targets　could　suppress　immune　responses,　leading　to　elevated　neoantigen　expression　proportion　in　tumor　cells.　Furthermore,　we　discovered　an　immune　escape　mechanism　that　tumors　could　become　more　inconspicuous　by　evolving　subclones　with　less　immunogenicity.　We　observed　that　smaller　clonal　mutation　clusters　with　higher　immunogenicity　in　tumor　were　more　likely　to　involve　in　clonal　evolution.　Based　on　identified　neoantigen　profiles,　we　also　discovered　series　of　neoantigenic　hotspot　genes,　which　could　serve　as　potential　actionable　targets　in　future.　Conclusions:　Our　results　revealed　the　landscape　of　HCC　neoantigens　and　discovered　two　clinically　relevant　subgroups　with　distinct　neoantigen　expression　patterns,　suggesting　the　neoantigen　expression　should　be　fully　considered　in　future　immunotherapeutic　interventions.