The enhancement of antibacterial activity of beta-lactam antibiotics by polyoxometalates against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) was investigated by using K6[P2W18O62] . 14H2O (P2W18), K4[SiMo12O40] . 3H2O (SiMo12), and K7[PTi2W10O40] . 6H2O (PTi2W10). Susceptibility test by a beta-lactam-disk method showed the synergistic effect of the polyoxometalates in combination with oxacillin against both MRSA and VRSA. Energy dispersive X-ray analysis of the strain treated with P2W18 revealed localization of the polyoxometalate-tungsten atoms at the periphery of the cell, and the biological reduction of P2W18 and SiMo12 proceeded within both cells of MRSA and VRSA as far as they keep alive. These results indicate that the polyoxometalates can penetrate through the cell wall consisting of peptidoglycan layers and reach cytoplasmic membrane. The inhibitory effect of the polyoxometalates on both mecA- and pbp-induced mRNA expression of both MRSA and VRSA cells, verified by the RT-PCR-electrophoresis analysis, is observed, and the mechanism of the synergistic effect by the polyoxometalates is discussed in terms of the depression of penicillin-binding protein 2' (PBP2') coded by mecA gene.