In the present study, the effects of antihistamines on inwardly rectifying potassium (Kir) channels expressed in Xenopus oocyte were investigated using two-electrode voltage clamp technique. Firstly, effects of antihistamines on two members of Kir2.0 sub-family, Kir2.1 and Kir2.3 were compared. For antihistamines that selectively block histamine H 1 receptor, the first-generation antihistamines mepyramine and diphenhydramine inhibited Kir2.3 current by 25.0±2.9% and 17.3±0.7% at concentrations of 100 μM, respectively. In contrast, the second- and third-generation antihistamines astemizole and desloratadine were completely devoid of any inhibitory effect on Kir2.3 current. Histamine H 2 receptor antagonist cimetidine, at 100 μM, failed to inhibit Kir2.3 current. On the other hand, Kir2.1 current was not sensitive to any of these drugs. The mepyramine-induced inhibition of Kir2.3 current was significantly reduced by a single point mutation in Kir2.3 (Kir2.3(I213L)), which enhances Kir2.3-PIP 2 interaction. Secondly, the effect of mepyramine was also tested on Kir3.4 ⁎ , another member of Kir family. 100 μM mepyramine produced a 30.3±4.6% inhibition on Kir3.4 ⁎ current. These results suggest that the first-generation histamine H 1 receptor antagonists selectively inhibit Kir currents. The inhibitory effect of antihistamines on Kir currents may be involved in their neuronal and cardiac toxic effects caused by drug overdosing.