HCC (hepatocellular carcinoma) is often diagnosed at an advanced stage with poor prognosis. Peripheral blood may be useful in cancer classification, and therefore we investigated the gene expression found by Affymetrix HG-U133 Plus2.0 microarray, with samples from nine HCC patients and five healthy NC (normal controls). A total of 726 probe sets showed significant differences based on the criteria of P<0.05 and absolute fold change >2. The genes were related to many biological functions, including immune response, transcription regulation and metabolism processes. Ten genes [IL-8 (interleukin 8), GOS2 (G0/G1 switch gene 2), CXCR4 (CXC chemokine receptor 4), FOS, RPS24 (40S ribosomal protein S24), HAP90AA1, PFDN5, RPL27, GZMA and PFN1] showing significant differences were confirmed by real-time PCR in 54 HCC patients and 56 healthy NC. Seven genes [IL-8, GOS2, CXCR4, FOS, RPS24, HSP90AA1 (heat shock protein 90AA1) and PFN1] showed significant difference both in RT—PCR (reverse transcription—PCR) and microarray. Expression of IL-8 and FOS proteins was up-regulated in HCC compared with healthy controls. A gene signature in peripheral blood which can distinguish HCC patients and healthy controls may have been identified.