Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia. Although surgical treatment may be curative in the early stages, the five-year overall survival rate is only 50-70%. Advances in genomics and transcriptomics have greatly improved our understanding of the molecular mechanisms of HCC genesis and progression, HCC treatment remains a unique clinical challenge, and targeted therapies for HCC subpopulations and corresponding predictive biomarkers are urgently required. Here, we present the largest characterization effort involving the proteomic and phosphoproteomic profiling of 110 paired clinical HBV-related early HCC tumor and non-tumor tissues (Barcelona Clinic Liver Cancer stages 0 and A). The quantitative proteomic data highlighted the heterogeneity in early-stage HCC and were used to stratify the cohort into three subtypes (i.e., S-I, S-II and S-III) with different clinical outcomes. S-III, which was characterized by disrupted cholesterol homeostasis, had the worst overall survival and greatest risk of a poor prognosis after first-line surgery. Moreover, the knockdown of the S-III specific signature SOAT1 altered the distribution of cellular cholesterol and effectively suppressed HCC proliferation and migration. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. Thus, our study identifies the proteomic landscape in early HCC, and the patterns of protein signatures and pathways that are altered in proteomic subtypes of HCC. The drug-targetable proteins that are identified by proteomic alterations may provide a powerful tool for identifying patients with HCC subtypes associated with a poor prognosis, and who might benefit from further targeted treatment, moving us towards the era of proteomics-driven precision medicine.