Sixteen pairs of two-component regulatory systems are identified in the genome of Staphylococcus epidermidis ATCC12228 strain, which is newly sequenced by our laboratory for Medical Molecular Virology and Chinese National Human Genome Center at Shanghai, by using bio-informatics analysis. Comparative analysis of the two-component regulatory systems in S. epidermidis and that of S. aureus and Bacillus subtilis shows that these systems may regulate some important biological functions, e.g. growth, biofilm formation, and expression of virulence factors in S. epidermidis. Two conserved domains, i.e. HATPase-c and REC domains, are found in all 16 pairs of two-component proteins. Homologous modelling analysis indicates that there are 4 similar HATPase-c domain structures of histidine kinases and 13 similar REC domain structures of response regulators, and there is one AMP-PNP binding pocket in the HATPase-c domain and three active aspartate residues in the REC domain. Preliminary experiment reveals that the bioinfor-matics analysis of the conserved domain structures in the two-component regulatory systems in S. epidermidis may provide useful information for discovery of potential drug target.