Abstract Unidirectional and net Na + fluxes modified by changes in internal Na + concentration ([Na +] i) were studied in human red blood cells incubated in K +-free solutions containing 10 −4 M ouabain. An increase in [Na +] i brought about (a) a reduction in net Na + gain, (b) no change in Na + influx, (c) a reduction in the rate constant for Na + efflux and (d) an increase in Na + efflux. Similar reductions in net Na + gain were observed when the changes in [Na +] i were carried out at constant [K +] i. In addition, the rate constant for 42K + efflux was not affected by changes in [Na +] i. The electrical membrane potential (as determined from the chloride distribution ratio) was also constant. Furosemide (10 −3 M) increased the net Na + gain in high [Na +] i cells and had no effect on those with low [Na +] i. External K + at 50 mM concentration reduced Na + efflux and increased Na + influx: the magnitude of these effects was dependent on the intracellular Na +. The reduction in net Na + gain as [Na +] i increased was unaffected by depletion of cellular ATP to values below 10 μmol/l cells, and this effect was independent of the depletion method used.