Background & Aims Des-gamma-carboxy prothrombin (DCP) and Lens culinaris agglutinin–reactive fraction of α-fetoprotein (AFP-L3) are surveillance markers used to detect hepatocellular carcinoma (HCC) in Japan. This study evaluated their utility, alone or in combination, in a North American population. Methods Patients with hepatitis C virus–related cirrhosis were followed up prospectively for 2 years. Results Of 372 patients, HCC developed in 34 of 298 who were free of HCC at entry. The overall sensitivity, specificity, and positive and negative predictive values for only AFP (>20 ng/mL) were 61%, 71%, 34%, and 88%, respectively; for only AFP-L3% (>10) were 37%, 92%, 52%, and 85%, respectively; and for only DCP (>7.5 ng/mL) were 39%, 90%, 48%, and 86%, respectively. Values increased when AFP values were combined with AFP-L3% and DCP to 77%, 59%, 32%, and 91%, respectively. Among patients with increases in AFP levels to 20 to 200 ng/mL, AFP-L3% and DCP were highly specific markers (86.6% and 90.2%, respectively). Of 29 HCC patients with AFP levels less than 20 ng/mL, 13 had increased levels of AFP-L3% or DCP. Increased alanine aminotransferase levels were associated with increased total AFP but not AFP-L3% or DCP levels. Both AFP-L3%– and DCP-positive patients showed significant differences in lower cumulative HCC-free rates compared with the overall group ( P < .0001 and P = .0005, respectively). Conclusions AFP-L3% and DCP levels have higher correlation values with an absence of HCC, as well as a higher specificity and negative predictive value, than total AFP. Although this combination of markers only marginally improves surveillance for early HCC, it could identify individuals with negative imaging results who would benefit from follow-up evaluation.