Several types of aggressive cancers, including hepatocellular carcinoma (HCC), often arise as a multifocal primary tumor. This suggests a high rate of premalignant changes in noncancerous tissue before the formation of a solitary tumor. Examination of the messenger RNA expression profiles of tissue samples derived from patients with cirrhosis of various etiologies by complementary DNA (cDNA) microarray indicated that they can be grossly separated into two main groups. One group included hepatitis B and C virus infections, hemochromatosis, and Wilson's disease. The other group contained mainly alcoholic liver disease, autoimmune hepatitis, and primary biliary cirrhosis. Analysis of these two groups by the cross-validated leave-one-out machine-learning algorithms revealed a molecular signature containing 556 discriminative genes (P < .001). It is noteworthy that 273 genes in this signature (49%) were also significantly altered in HCC (P < .001). Many genes were previously known to be related to HCC. The 273-gene signature was validated as cancer-associated genes by matching this set to additional independent tumor tissue samples from 163 patients with HCC, 56 patients with lung carcinoma, and 38 patients with breast carcinoma. From this signature, 30 genes were altered most significantly in tissue samples from high-risk individuals with cirrhosis and from patients with HCC. Among them, 12 genes encoded secretory proteins found in sera. In conclusion, we identified a unique gene signature in the tissue samples of patients with cirrhosis, which may be used as candidate markers for diagnosing the early onset of HCC in high-risk populations and may guide new strategies for chemoprevention.