Infection with hepatitis C virus (HCV) is characterized by inflammatory liver damage and a long viral persistence associated with an increased risk of developing hepatocellular carcinoma (HCC). Intercellular adhesion molecule-1 (ICAM-1) plays a key role during liver inflammation and also expressed in HCC. Its cellular expression is associated with the release of soluble form (sICAM-1) in the peripheral blood. The process of angiogenesis plays a critical role in liver damage-associated HCV infection and in tumor growth and metastasis. Vascular Endothelial Growth Factor (VEGF) is an important angiogenic factor regulating tumor angiogenesis. This study aimed at investigating the influence of HCV infection on serum profile of sICAM-1 and VEGF in patients with hepatitis C and HCC and their diagnostic value as useful markers reflecting progressive liver damage and development of HCC. Serum levels of sICAM-1 and VEGF were determined in the serum of fifteen HCV infected patients, fifteen HCV-positive patients with superimposed HCC as well as ten healthy control subjects by enzyme linked immunosorbent assay. HCV RNA copy numbers were analyzed by Real-time polymerase chain reaction using TaqMan probe technology. Alpha-fetoprotein levels and serum aminotransferases activities were also measured. The group of patients with hepatitis C and superimposed HCC had significantly higher sICAM-1 and VEGF values than HCV infected patients (1178.113 +/- 631.87 vs. 313.67 +/- 82.72 & 320.88 +/- 117.99 vs. 132.45 +/- 91.56, p < 0.001 respectively). In comparison to healthy subjects, HCV infected patients showed dramatically elevated serum levels of VEGF (132.45 +/- 91.56 vs. 7.76 +/- 7.41, p < 0.001). On the other hand, sICAM-1 levels were elevated in patients with HCV as compared with healthy controls, but this did not reach statistical significance (313.67 +/- 82.72 vs. 230.3 +/- 47.4, p > 0.05). A highly significant correlation was found between VEGF and sICAM-1 levels in all patients (r = 0.731, p < 0.001) also between VEGF, sICAM-1 and AFP (r = 0.473, p < 0.001, r = 0.690, p < 0.001, respectively) as well as between sICAM-1 and AST activities (r = 0.367, p < 0.05). A weak correlation was found between the level of viremia and VEGF, sICAM-1 levels, yet this did not reach statistical significance (r = 0.312, p = 0.09 & r = 0.228, p > 0.05 respectively). The sensitivity of HCC detection using AFP alone was 93.3%. It yielded 100% detection sensitivity when combined with sICAM-1 and/or VEGF with diagnostic accuracy reaching 96.67%. In conclusion, HCV infection and the development of HCC on top greatly affect the serum profile of VEGF and sICAM-1. VEGF as it stimulates endothelial cell growth, it could modulate the expression of sICAM-1 and both could be considered as convenient markers of progressive liver damage, endothelial activation and therefore could improve detection and management of HCC.