Background/Aims. Voltage-dependent potassium channels (Kv1.3) are predominantly expressed in lymphocyte plasma membranes. These channels are critical for the activation and proliferation of lymphocytes. Since second-generation antihistamines are lipophilic and exert immunomodulatory effects, they are thought to affect the lymphocyte Kv1.3-channel currents. Methods. Using the patch-clamp whole-cell recording technique in murine thymocytes, we tested the effects of second-generation antihistamines, such as cetirizine, fexofenadine, azelastine, and terfenadine, on the channel currents and the membrane capacitance. Results. These drugs suppressed the peak and the pulse-end currents of the channels, although the effects of azelastine and terfenadine on the peak currents were more marked than those of cetirizine and fexofenadine. Both azelastine and terfenadine significantly lowered the membrane capacitance. Since these drugs did not affect the process of endocytosis in lymphocytes, they were thought to have interacted directly with the plasma membranes. Conclusions. Our study revealed for the first time that second-generation antihistamines, including cetirizine, fexofenadine, azelastine, and terfenadine, exert suppressive effects on lymphocyte Kv1.3-channels. The efficacy of these drugs may be related to their immunomodulatory mechanisms that reduce the synthesis of inflammatory cytokine.