More than 70% of hepatocellular carcinoma (HCC) cases develop as a consequence of liver cirrhosis (LC). Here we have evaluated the diagnostic potential of four serum biomarkers, and developed models for HCC diagnosis and differentiation from LC patients. Serum levels of α-fetoprotein (AFP), AFP-L3, des-γ-carboxy prothrombin (DCP), and Golgi protein 73 (GP73) were analyzed in 114 advanced HCC patients, 81 early stage HCC patients, and 152 LC patients. Multilayer perceptron (MLP) and radial basis function (RBF) neural networks were used to construct the diagnostic models. Using all stages, HCC diagnostic models had a higher sensitivity (>70%) than the individual serum biomarkers, whereas only early stage HCC diagnostic models had a higher specificity (>80%). The early stage HCC diagnostic models could not be used as HCC screening tools due to their low sensitivity (about 40%). These results suggest that a combination of the two models might be used as a screening tool to distinguish early stage HCC patients from LC patients, thus improving prevention and treatment of HCC.