The ability of isolated human erythrocytes to exchange Na+ for K+ via (Na+ + K+)-ATPase was used to study the characteristics and interactions of the transport of both alkali metal and synthetic monovalent cations. Both efflux and influx studies were carried out and the results showed that: (1) Efflux of 22Na+ from human erythrocytes was stimulated by the addition of either of K+, or Tl+ at 10 mM and inhibited by the addition of ouabain. Unlabeled K+ and the addition of [99Tc(dmpe)2 X Cl2]+ (dmpe, 1,2-bis(dimethylphosphino)ethane) at 5 mM had no effect on 22Na+ efflux. (2) Influx of 42K+ was inhibited by the addition of ouabain, unlabeled K+, or Tl+. 201Tl+ influx was more rapid and of a greater magnitude than 42K+ influx. [99Tc(dmpe)2 X Cl2]+ had no effect on 42K+ uptake. (3) Influx of 201Tl+ was inhibited by ouabain and by the addition of unlabeled Tl+. Addition of [99Tc(dmpe)2 X Cl2]+ at 5 mM resulted in an inhibition of 201Tl+ influx. (4) [99Tc(dmpe)2 X Cl2]+ influx resembled that of 42K+ with respect to rate and magnitude. Influx of [99mTc(dmpe)2 X Cl2]+ was shown to be unaffected by ouabain, unlabeled K+ or Tl+. Addition of 5 mM [99Tc(dmpe)2 X Cl2]+ initially had no effect on [99mTc(dmpe)2 X Cl2]+ influx, however, a time-dependent stimulation of the influx of the [99mTc(dmpe)2 X Cl2]+ was observed. We conclude that the influx of the various alkali, metal and synthetic monovalent cations into erythrocytes is mediated by different mechanisms. Most clearly, the influx of [99mTc(dmpe)2 X Cl2]+ is not by a mechanism similar to that of utilized by K+ or Tl+.