Serum alpha fetoprotein (AFP) is a commonly used marker in the screening for hepatocellular carcinoma. This study aims to evaluate the value of AFP as an early predictor of the evolution of chronic hepatitis C. In a retrospective study on 116 HCV-infected patients (62.9% females, mean age 49.13 ± 1.73 years), increased levels of serum AFP (> 7 ng/mL) were found in 39.7% of cases. High serum AFP levels were more frequently detected in older patients and in those with severe fibrosis and cirrhosis (62.2% and 76.9% respectively vs. 11.6% in those without significant fibrosis, p = 0.0001). Increased AFP levels were significantly associated with markers of hepatic cytolysis (ALT- r = 0.245, p = 0.009 and AST r = 0.441, p = 0.0001) and cholestasis (GGT level-r = 0.947, p = 0.000 1), but not with HCV viral load. A predictive model based on AFP level and routinely monitored biochemical markers of liver fibrosis and necroinflammatory activity can be a useful clinical tool in chronic HCV infection.