Introduction: Hypoxia is a major feature of hepatocellular carcinoma (HCC). The master hypoxamir, MIRNA-210, controls many carcinogenic pathways. Hypoxia can affect mitochondrial DNA copy number (MTCN), which could impair many mitochondrial functions, including electron transport chain (ETC). Vitamin K2 (VK2) is crucial for preserving ETC integrity. Aim of the study: To evaluate the role of MTCN, MIRNA-210 and VK2 in HCC prediction, prevention and personalized treatment. Methodology: 60 cirrhotic patients with HCC (group I) classified into three sub-groups according to BCLC staging (20 patients each); Group (IA): Stages 0/A, (IB): stage B and (IC): stages C/D. Group II comprised 60 cirrhotic patients without HCC. Group III included 60 healthy controls. All participants were evaluated clinically, circulating MIRNA-210 expression and MTCN were assessed by real time polymerase chain reaction and VK2 levels were measured by ELISA. Results MIRNA-210 was higher in group I compared to other groups (P < 0.001). VK2 and MTCN were lower in group I than in other groups (P = 0.001 in both parameters). MIRNA-210 was higher in subgroup 1C than other sub-groups (P < 0.001). Both VK2 and MTCN were lower in subgroup IC than in subgroups IA and IB (P = 0.042, P < 0.001 respectively). In group I, Both VK2 and MTCN were negatively correlated with MIRNA-210 (p = 0.001, p < 0.001 respectively), but positively correlated with each other (p < 0.001). Same pattern followed in subgroups of group I and in group II. Conclusion Results suggest a potential predictive role of the studied markers in HCC, hence the possibility of early prevention and personalized treatment.