Hepatocellular carcinoma (HCC) is characterized by multiple somatic mutations, including DNA rearrangements, that affect many cell-growth regulatory pathways. Many genes differentially expressed in HCC have been reported previously, but the patterns of expression varied significantly between patients who bore different risk factors for HCC. To identify genes whose differential expression could serve as a “signature” for diagnosis and prognosis of HCC, we performed analyses of differentially expressed genes in three cases of HCC with different risk factors using the Atlas Human Cancer cDNA Expression Arrays. Among all 597 genes present on the array, only three were found to be coordinately differentially expressed in all three HCC cases, in agreement with published data. These three genes, Cu/Zn superoxide dismutase, osteonectin/secreted protein acidic and rich in cysteine, and matrix metalloproteinase 14, could serve as candidates for the HCC “signature.” Ten genes were found to be coordinately differentially expressed in only two of three tested HCC cases. On the other hand, many genes that had been reported previously as differentially expressed in HCC failed to show the described pattern of expression in this group. The results of this study confirm the great variability in gene-expression patterns in HCC and establish the utility of the array technology for identifying both the HCC signature genes and individual gene-expression patterns for purposes of patient-oriented therapy. © 2002 Wiley-Liss, Inc.