AIM: To study the difference in gene expression between solitary large hepatocellular carcinoma (SLHCC) and nodular hepatocellular carcinoma (NHCC). METHODS: Polymerase chain reaction (PCR) products of 8464 human genes were spotted on a chip in array. DNAswere then fixed on a glass plate. Total RNA was isolated from freshly excised human SLHCC (n=7) and NHCC (n=15) tissues, and was reversely transcribed to cDNAs with the incorporation of fluorescent dUTP for preparation of hybridization probes. The mixed probes were then hybridizedto the cDNA microarray. After highly stringent washing, cDNA microarray was scanned for the fluorescent signalsto display the difference between the two kinds of HCC. In addition, the expression of RhoC and protocadherin LKC was also detected with the reverse transcriptase polymerase chain reaction (RT-PCR) method. RESULTS: Among the 8464 human genes, 668 (7.89%)genes were expressed differentially at the mRNA levels between SLHCC and NHCC. Three hundred and fifty five (4.19%) genes, including protocadherin LKC, were upregulated,whereas 313 (3.70%) genes, including RhoC, were down-regulated. The mRNA expression levels of RhoC and protocadherin LKC were confirmed by RT-PCR. Analysis of differentially expressedgenes confirmed that our molecular data obtained by cDNA microarray were consistent with the published biochemical and clinical observations ofSLHCC and NHCC. CONCLUSION: cDNA microarray is an effective technique in screening the difference in gene expression between SLHCC and NHCC. Many of these differentially expressed genes are involved in the invasion and metastasis of HCC.Further analysis of these genes will help to understand thedifferent molecular mechanisms of SLHCC and NHCC.