Introduction　Intra-tumoral　heterogeneity　is　a　prominent　characteristic　of　hepatocellular　carcinoma　(HCC).　However,　it　remains　unexplored　whether　intra-tumoral　transcriptomic　differences　can　capture　crucial　information　regarding　HCC　evolution　and　be　utilized　to　derive　a　predictive　signature　for　patient＇s　clinical　trajectories.Methods　We　quantified　transcriptomic　heterogeneity　using　four　multiregional　HCC　cohorts　comprising　172　samples　from　37　patients,　and　validated　transcriptomic　heterogeneity　and　spatial　dynamics　using　multiregional　single-cell　transcriptomic　profiling　of　110,817　cells　from　34　liver　specimens.　The　HCC　evolutionary　signature　(HCCEvoSig)　was　developed　and　assessed　across　six　cross-platform　HCC　cohorts.Results　Genes　exhibiting　high　intra-　and　inter-tumor　expression　variation　were　significantly　enriched　in　a　gene　set　associated　with　HCC　prognosis,　from　which　we　developed　and　validated　a　reproducible　and　robust　transcriptomic　signature,　HCCEvoSig.　Multiregional　single-cell　data　confirmed　the　high　intra-　and　inter-tumoral　heterogeneity　of　HCCEvoSig　genes　across　different　cell　types,　and　importantly,　demonstrated　that　the　dysregulation　of　HCCEvoSig　genes　exhibited　a　geospatially　gradual　transition　from　the　non-tumor　region　to　the　tumor　border　and　tumor　core,　as　well　as　from　non-malignant　to　malignant　epithelial　cells.　HCCEvoSig　showed　significant　positive　associations　with　adverse　features　of　HCC,　and　a　high　HCCEvoSig　risk　score　predicted　increased　risks　of　disease　progression　and　mortality,　independent　of　established　clinicopathological　indices.　Furthermore,　HCCEvoSig　outperformed　15　published　signatures　in　discriminative　ability　and　prognostic　accuracy,　particularly　regarding　1-year　survival　rates.　Notably,　HCCEvoSig　demonstrated　predictive　utility　for　responses　to　immunotherapy　and　trans-arterial　chemoembolization.　Additionally,　we　established　a　well-calibrated　predictive　nomogram　that　integrates　HCCEvoSig　and　TNM　stage　to　generate　an　individualized　numerical　probability　of　mortality.Conclusion　Our　study　reveals　that　regional　transcriptional　heterogeneity　within　tumors　is　substantial　enough　to　capture　survival　signals,　and　the　constructed　and　validated　HCCEvoSig　provides　reliable　prognostic　information　for　HCC　patients.