Pseudoephedrine is a sympathomimetic drug in which its structure is similar to amphetamine. Although pseudoephedrine is not as potent as amphetamine, it has been reported that the actions of pseudoephedrine on the central nervous system via dopamine release resemble to amphetamine. Changes of dopamine function can induce malfunction of glutamatergic system because there are well-documented interactions between glutamate/N-methyl-D-aspartate (NMDA) receptors and dopaminergic system. Therefore, the aim of this study was to investigate the effects of acute and chronic pseudoephedrine administration on NMDA receptors in hippocampal formation. Immunohistochemistry was used to determine the alteration of NMDA receptor density in rat hippocampus and dentate gyrus following acute and chronic pseudoephedrine administration. The density of NMDA receptors was increased significantly (p<0.005) in the dentate gyrus of animals treated with pseudoephedrine chronically when compared with the acute and control groups. Similarly, the density of NMDA receptors in an acute group was also higher than the control group (p<0.01). These results indicate that pseudoephedrine could induce an increase of NMDA receptors in the dentate gyrus. This might be a compensatory effect of NMDA receptor in response to the degeneration or loss of glutamatergic neurons.