1. The effects of external Li on Na and K efflux as well as those on K influx were studied in high Na muscles from Rana pipiens. 2. In the absence of external Ba, substitution of K-free Li for K-free Mg resulted in an increase of both Na and K efflux. The additional of ouabain produced an inhibition of Na efflux and at the same time a marked increase in the efflux of K. 3. K permeability was greatly reduced by adding 2 mM-Ba to the incubation solutions. Under these conditions, Li gave rise to a ouabain sensitive Na efflux which was 57% of that in the absence of Ba. On the other hand, the efflux of K was only slightly increased and was not affected further by ouabain. 4. The activation curves of Na efflux against the stimulating cation concentration in Na-free Mg-Ba Ringer followed a more or less hyperbolic function for both K and Li. While half-maximal activation was attained at higher concentrations of Li than of K, the maximal efflux in Li was smaller than in K. 5. The extra Na efflux produced by K was increased when Li was added to the media. This increment was not a simple additive effect and was independent of the Li concentration. In addition, at some concentrations Li increased the ouabain-sensitive K influx, whereas at others it reduced it. 6. Reversible changes in membrane permeability to monovalent cations were accomplished by incubating the muscles in the presence of Nystatin, 50 mug/ml. When internal K was reduced to values around 1-2 mumole/g (using Li as a replacement), thus minimizing the possibility of K leaking out of the cells, both Ko and Lio were able to promote a ouabain-sensitive extra efflux of Na. 7. The residual Na efflux in (K+Na)-free solutions was not affected by the removal of Ca from the media in either Mg or Li solutions, both in the absence and the presence of Ba. On the other hand, the values for the residual efflux were higher in Mg (0-00228 min-1) than in Li (0.00135 min-1). 8. These results fully support the notion that Li ions have a K-like activating action on the Na pump in muscles. In addition, they suggest that some other kind of interaction may exist between Li and the Na-K pump.