Objectives: To evaluate the value of estimating serum Des-γ-carboxyprothrombin (DCP), lens culinaris agglutinin-reactive alpha-fetoprotein (AFP) percentage of total AFP concentration (AFP-L3%) and/or total AFP as predictors for hepatocellular carcinoma (HCC) grades. Patients & Methods: The study included 26 patients with HCC and 20 controls. All patients underwent complete clinical examination, radiologic and laboratory assessment. Blind liver biopsies were done for histopathological examination and grading. A fasting blood samples were obtained from all patients and controls for ELISA estimation of DCP and liquid-phase binding assay for AFP and AFP-L3% serum levels. Results: Liver biopsy histopathological grading of HCC defined 13 patients with well differentiated, 7 with moderately differentiated, and 6 with poorly differentiated HCC. Serum levels of the three parameters were significantly higher in patients compared to controls, and in patients had poorly compared to patients had well differentiated HCC; on the other hand, the serum levels of DCP and AFP-L3% were significantly higher in patients had poorly compared to those had moderately differentiated HCC, whereas, the serum DCP levels were significantly higher, but the serum AFP and AFP-L3% levels were non-significantly higher, in patients had moderately differentiated HCC compared to those had well differentiated HCC. Stepwise regression analysis defined serum DCP levels, alone or in combination with other markers, as a significant predictor for the extent of pathological advancement in three models of statistical analyses, and the ROC curve analysis supported its specificity followed by AFP-L3% with significant difference compared to the null hypothesis, while AFP alone was non-significant as specific marker. Conclusion: A panel of DCP and AFP-L3% provided a high diagnostic yield for the presence of HCC as well as for the prediction of its pathological grading, and thus could be used in conjunction with other non-invasive diagnostic modalities to avoid unnecessary liver biopsies, especially in compromised or early staged patients.