Objective To investigate the differential gene expression in chronic hepatitis B (CHB) patients with typical syndromes of traditional Chinese medicine ( TCM) syndromes, and to explore the relationship between TCM syndromes and gene expression. Methods Peripheral blood samples were collected from CHB patients and healthy volunteers before treatment. After total RNA of leukocytes was isolated, the gene expression profiles were detected by microarray. The expression levels of partial genes were tested by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) . Results Microarray analysis results showed that there were significant differences of gene expression between CHB patients and healthy volunteers, and among CHB patients with the syndrome of liver-qi stagnation and spleen deficiency, syndrome of damp-heat accumulation, and syndrome of liver-kidney yin deficiency. The results of gene ontology ( GO) and signal pathway analysis between the healthy control and CHB patients with various syndromes showed that the specially-regulated genes of CHB patients with liver-qi stagnation and spleen deficiency were mainly related to cytokinetic process, those in patients with dampness-heat accumulation were mainly related to the positive regulation of lipid storage, and those of patients with liver-kidney yin deficiency were mainly related to the activities of nitric oxide synthase regulator. The real time RT-PCR for partial genes presented the similar results with those of gene microarray. Conclusion There are specific expression profiles of differential genes and significant differential genes in CHB patients with the syndrome of liver-qi stagnation and spleen deficiency, syndrome of damp-heat accumulation, and syndrome of liver-kidney yin deficiency, which may be the molecular foundation for the classification of TCM syndromes of CHB patients.