The lymphocyte potassium channel Kv1.3 is widely regarded as a promising new target for immunosuppression. To identify a potent small-molecule Kv1.3 blocker, we synthesized a series of 5-phenylalkoxypsoralens and tested them by whole-cell patch clamp. The most potent compound of this series, 5-(4-phenylbutoxy)psoralen (Psora-4), blocked Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC 50 value of 3 nM, by preferentially binding to the C-type inactivated state of the channel. Psora-4 is the most potent small-molecule Kv1.3 blocker known. It exhibited 17-to 70-fold selectivity for Kv1.3 over closely related Kv1-family channels (Kv1.1, Kv1.2, Kv1.4, and Kv1.7) with the exception of Kv1.5 (EC 50 , 7.7 nM) and showed no effect on human ether-a-go-go-related channel, Kv3.1, the calcium-activated K ϩ channels (IKCa1, SK1-SK3, and BK Ca ), or the neuronal Na V 1.2 channel. In a test of in vivo toxicity in rats, Psora-4 did not display any signs of acute toxicity after five daily subcutaneous injections at 33 mg/kg body weight. Psora-4 selectively suppressed the proliferation of human and rat myelin-specific effector memory T cells with EC 50 values of 25 and 60 nM, respectively, without persistently suppressing peripheral blood naive and central memory T cells.