ACTIVE LI EFFLUX FROM HUMAN ERYTHROCYTES WAS SHOWN TO BE MEDIATED BY THE NA/K PUMP: (i) intracellular Li (Li(c)) activated ouabain-sensitive K influx, and (ii) a portion of the Li efflux required external K and was inhibited by ouabain. In activating K influx, Li(c) interacts with the pump like Na rather than like K-depleting the cells of orthophosphate inhibited activation of K influx by intracellular K (K/K exchange) but did not inhibit Li-activated K influx. (To show these interactions of Li(c) with the Na/K pump, p-chloromercuribenzenesulfonate or nystatin was used to allow replacement of intracellular Na and K with Li and choline.) From kinetic studies of the pump, it was shown that the apparent affinity of the intracellular aspect of the Na/K pump for Li was an order of magnitude less than that for Na. From simultaneous measurements of ouabain-sensitive net fluxes of Li and K in Na-free cells, it was shown that the pump-mediated K influx and Li efflux were coupled. The stoichiometry of the coupling ratio was close to 1:1 for Li:K, different from the coupling ratio of 3:2 for Na:K in the pump's normal mode of operation. It had been shown previously that the Na/K pump in human erythrocytes mediates active Li influx. Because it also mediates active Li efflux, the molecular mechanisms for distinguishing between Na and K must be qualitatively different at the internal and external aspects of the pump. The possible relevance of the results of this study to manic depressive illness and Li therapy is discussed.