Mortality due to hepatocellular carcinoma (HCC) has not improved over the last 20 years. This is in part due to the poor performance of available tumor markers leading to delays in diagnosis. Des-gamma carboxy-prothrombin (DCP) has been reported to be more sensitive and specific for the diagnosis of HCC in Japanese patients compared with alpha-fetoprotein (AFP). We conducted a cross-sectional case control study to evaluate whether DCP is more sensitive and specific than AFP for differentiating HCC from nonmalignant liver disease in a cohort of American patients from a single referral center. Four groups were studied: G1, normal healthy subjects; G2, patients with noncirrhotic chronic hepatitis; G3, patients with compensated cirrhosis; and G4, patients with histologically proven HCC. A total of 207 subjects were enrolled. Both DCP and AFP levels increased progressively from G1 to G4, but DCP values had less overlap among the groups than AFP. ROC curve indicated that a DCP value of 125 mAU/mL yielded the best sensitivity (89%; 95% CI, 77%-95%) and specificity (95%; 95% CI, 82%-96%) for differentiating patients with HCC from those with cirrhosis and chronic hepatitis. The optimal AFP cutoff value was 11 ng/mL and was inferior to the DCP value of 125 mAU/mL, the area under the ROC curves being 0.928 versus 0.810, respectively (P =.002). In conclusion, DCP was more sensitive and specific than AFP for differentiating HCC from nonmalignant chronic liver disease. Prospective studies to evaluate the role of DCP in early HCC are underway.