The tumor microenvironment (TME) was usually studied in tumor tissue and in relation to only tumor progression, with little involved in occurrence, recurrence and metastasis of tumor. Thus, a new concept "peritumor microenvironment (PME)" was proposed in the proteomic characterization of peritumor liver tissues in human hepatocellular carcinoma (HCC). The PME for occurrence (PME-O) and progression (PME-P) were almost totally different at proteome composition and function. Proteins for occurrence and progression rarely overlapped and crossed. Immunity played a central role in PME-O, whereas inflammation, angiogenesis and metabolism were critical in PME-P. Proteome profiling identified three PME subtypes with different features of HCC. Thymidine phosphorylase (TYMP) was validated as an antiangiogenic target in an orthotopic HCC mouse model. Overall, the proteomic characterization of the PME revealed that the entire processes of HCC occurrence and progression differ substantially. These findings could enable advances in cancer biology, diagnostics and therapeutics.