An accurate assessment of liver fibrosis is very important in order to predict the prognosis and to start the appropriate therapy to prevent disease progression. Several biochemical markers have been proposed as indicators of the change from chronic hepatitis to cirrhosis. This study was carried out on 126 serum samples pathologically divided into two groups. A, the fibrotic group with different stages (F1-F3) consists of 114 patients (85 males and 29 females) with liver fibrosis associated with HCV infections (aged 50.6 ± 11.7 yrs.). B, the control group consists of 12 non-fibrotic (F0) individuals with HCV infection without fibrosis (aged 29.2 ± 5.2 yrs.), used as controls. The results revealed that the level of serum fibronectin increased in the all patients in the fibrotic group. Significant differences (p < 0.0001) were shown between non-fibrotic liver (F0), liver fibrosis (F1-F3). Fibronectin was positively correlated with age, ALT, AST, and bilirubin and negatively correlated with albumin. In conclusion, fibronectin fragment had been identified in serum a sample of fibrotic group at 90-kDa and its level was increased in these samples; while it was normal in non-fibrotic group. These data confirm the role of fibronectin as a pacemaker of fibrosis.