Background:　Clinically,　prophylactic　anti-recurrence　treatments　for　hepatocellular　carcinoma　(HCC)　patients　after　radical　surgery　are　extremely　limited.　Neoantigen　based　vaccine　can　generate　robust　anti-tumor　immune　response　in　several　solid　tumors　but　whether　it　could　induce　anti-tumor　immune　response　in　HCC　and　serve　as　a　safe　and　effective　prophylactic　strategy　for　preventing　postoperative　HCC　recurrence　still　remain　largely　unclear.　Methods:　Personalized　neoantigen　vaccine　was　designed　and　immunized　for　10　HCC　patients　with　high　risk　of　postoperative　recurrence　in　a　prime-boost　schedule.　The　safety　and　immune　response　were　assessed　through　adverse　events,　tissue　sequencing,　ELISpot,　TCR　sequencing.　The　clinical　response　was　evaluated　by　recurrence-free　survival　(RFS)　and　personalized　circulating　tumor　DNA　(ctDNA)　sequencing.　Results:　In　the　10　enrolled　patients,　no　obvious　adverse　events　were　observed　during　neoantigen　vaccinations.　Until　the　deadline　of　clinical　trial,　8　of　10　patients　were　confirmed　with　clinical　relapse　by　imaging,　the　other　2　patients　remained　relapse-free.　From　receiving　first　neoantigen　vaccination,　the　median　RFS　of　10　patients　were　7.4　months.　Among　7　patients　received　all　planned　neoantigen　vaccinations,　5　of　them　demonstrated　neoantigen-induced　T　cell　responses　and　have　significantly　longer　RFS　after　radical　surgery　than　other　5　patients　without　responsive　neoantigens　or　only　with　prime　vaccination　and　propensity　scores　matching　control　patients　(p　=　0.035).　Moreover,　tracking　personalized　neoantigen　mutations　in　ctDNA　could　provide　real-time　evaluation　of　clinical　response　in　HCC　patients　during　neoantigen　vaccination　and　follow　up.　Conclusion:　Personalized　neoantigen　vaccine　is　proved　as　a　safe,　feasible　and　effective　strategy　for　HCC　anti-recurrence,　and　its　progression　could　be　sensitively　monitored　by　corresponding　neoantigen　mutations　in　ctDNA,　and　thus　provided　solid　information　for　individualized　medicine　in　HCC.