The in vivo function of the erythrocyte Na + -Li + countertransport (SLC) is unknown. Whether SLC may reflect an operational mode of the widespread Na + -H + exchanger (NHE) or may otherwise be expression of an independent membrane transport, remains presently unclear. We explored the presence of 5-(N,N-dimethyl)-amiloride (DMA)-sensitive Li + pathways in human erythrocytes where the activity of the Na + pump, Na + -K + cotransport and anion exchange were suitably inhibited. A total of 0.02 mM DMA had no effect on SLC as expected, but gave a significant inhibition of Li + efflux into both Na + and Na + -free media. This DMA-sensitive Li + pathway, but not SLC, was significantly enhanced by hyperosmolar cell shrinkage, which is a characteristic feature of NHE. In conclusion, DMA-sensitive Li + pathways, possibly mediated by NHE, are present in erythrocytes and coexist with the DMA-insensitive, SLC. This finding supports the notion that SLC is independent of amiloride-sensitive NHE.