Background/Aims: Memantine (MEM) can block N-methyl-D-aspartate receptors non-competitively and is recognized to exert anti-inflammatory action. Whether MEM and other related compounds produce any effects on K⁺ currents in macrophages and in microglial cells is largely unknown. In this study, we investigated the effects of MEM and other related compounds on inwardly rectifying K⁺ current (I_K(IR)) in RAW 264.7 macrophages and in BV2 microglial cells. Methods: Patch-clamp recordings under whole-cell, cell-attached or inside-out configuration were performed in standard patch-clamp technique. MEM suppressed the I_K(IR) amplitude in a concentration-dependent manner with an IC₅₀ value of 12 µM. Results: This agent significantly slowed the inactivation time rate of I_K(IR) evoked with membrane hyperpolarization. In cells dialyzed spermine (10 µM), MEM-mediated inhibition of I_K(IR) no longer existed. MEM-suppressed activity is associated with a decrease in the slow component of mean open time and an increase in mean closed time, despite no detectable change in single-channel conductance of inwardly rectifying K⁺ (Kir) channels. Under current-clamp conditions, the addition of MEM resulted in membrane depolarization of RAW 264.7 cells. Similarly, in BV2 microglial cells, addition of MEM suppressed I_K(IR) as well as depolarized the membrane. However, neither C6 astrocytic cells nor Jurkat T-lymphoces were noted to display I_K(IR). Conclusion: The block by MEM of Kir2.1 channels is thus one of the important mechanisms underlying its actions on the functional activities of either macrophages or microglial cells, if similar findings occur in vivo.