Background: Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Aim of the work: To evaluate the usefulness of serum IL-6, serum VEGF, and VEGF/Platelets ratio in hepatocellular (HCC) diagnosis. Patients and methods: Fifty-eight cirrhotic patients with hepatocellular carcinoma were included in the study (51 males and 7 females) and 18 liver cirrhosis patients without HCC (15 male and 3 females were recruited as a control group. All patients were subjected to full medical history, clinical examination, laboratory investigations complete blood count, liver function tests, AFP, serum IL-6, serum VEGF and calculation of VEGF/platelets ratio. Results: Patients had significantly higher values of AFP (P=0.0001), IL-6 (P=0.004), VEGF (P=0.001) and VEGF/Platelets ratio (P=0.005) than cirrhotic patients without HCC (control group). Sensitivity and specificity of serum IL-6, VEGF and VEGF/Platelets in detecting HCC, was found to be 34.5 % & 94.4%, 43.1 % & 88.9% and 41.4 % & 88.9% respectively. Sensitivity and specificity of serum IL-6, serum VEGF and VEGF/platelets ratio for detection of portal vein thrombosis were 65.5% & 83.3%, 63,8% & 77,8%, and 58,6% & 72,2% respectively. There was significant positive correlation between VEGF and AFP (r=0.794, P=0.0001), VEGF/Plat and AFP (r=0.760, P=0.0001) and IL-6 and AFP (r=0.804, P= 0.0001). Conclusion: Serum IL-6, serum VEGF, and VEGF/platelets ratio are significantly higher in HCC patient than liver cirrhosis patients without HCC. The clinical utility of these biomarkers in HCC diagnosis is still doubtful because their sensitivity is not more than that of AFP. They may have a good role in detection of portal vein thrombosis (tumor invasion).