Synaptic plasticity is the foundation of learning and memory. CK2 phosphorylates many proteins related to it, but whether CK2 is directly involved in it has not been clear. Here, we examined the role of CK2 in synaptic plasticity in hippocampal slices using CK2 inhibitors, 5,6-dichloro-1-£o-D-ribofuranosylbenzimidazole (DRB) and 4,5,6,7-tetrabromobenzotriazole (TBB). The CK2 inhibitors significantly inhibited N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP). DRB inhibited NMDA receptor-mediated synaptic transmission but did not affect NMDA receptor-independent LTP. Therefore, NMDA receptors seem to be the primary targets for CK2. Both long-term depression (LTD) and LTP are induced by the influx of Ca2+ through NMDA receptors, but, surprisingly, LTD was not affected by CK2 inhibitors. We thought that the LTP-selective modulation by CK2 is caused by selective modulation of NMDA receptors, and had two hypothesises about the modulation of NMDA receptors: (i) CK2 selectively modulates NR2A subunits possibly related to LTP, but not NR2B subunits possibly related to LTD; (ii) CK2 selectively affects synaptic NMDA receptors, but not extrasynaptic NMDA receptors which activation sufficiently induces LTD. DRB decreased NMDA receptor-mediated synaptic transmission regardless of whether the selective NR2A subunit antagonist was present. Thus the former hypothesis seems unlikely. On the other hand, DRB decreased synaptic NMDA receptor responses in cultured hippocampal neurons but did not affect extrasynaptic NMDA currents after blockade of synaptic receptors. These results support the latter hypothesis and suggest that CK2 selectively affects LTP by selective modification of synaptic NMDA receptors in a receptor-location specific manner.