Natural killer (NK) cell tumoricidal and antimicrobial activities can be rapidly modulated by molecules that interact with membrane receptors. The discovery of NK cell depolarization induced by steroid-like Na+ channel agonists prompted a study of purified human NK cell excitability to a variety of steroids. Progesterone, but not estrogen, depolarized NK cells with concentration and time dependency. Excitability was measured by using flow cytometry and the anionic voltage-sensitive dye oxonol. Preincubation with the Na+ channel antagonist tetrodotoxin or removal of the extracellular Na+ blocked the response. Progesterone may rapidly change membrane potential, and eventually function, by acting on putative NK plasma membrane receptors coupled to Na+ conductances.