Erythrocyte concentrations and fluxes of sodium and potassium were investigated in normal white male subjects during dietary sodium restriction and repletion, each period lasting for 16 weeks. Intraerythrocyte sodium concentration decreased and red cell ouabain-sensitive 86Rubidium-uptake increased during dietary sodium restriction while no significant changes were observed in the total, furosemide-resistant and furosemide-sensitive sodium-efflux and the sodium, lithium-countertransport. The decrease in intraerythrocyte sodium concentration could have resulted from the observed increase in sodium, potassium-ATPase pump activity. The latter increase could have been secondary to the early decrease in a digitalis-like plasma inhibitor and the later increase could have been facilitated by the late rise in the intracellular adenosine triphosphate concentration, which is the energy supplier for this pump. During the subsequent first month of sodium repletion intraerythrocyte sodium concentration remained low. Red cell ouabain-sensitive 86Rubidium-uptake and adenosine triphosphate concentration remained elevated and returned to baseline only after 16 weeks. This long-term effect suggests either the involvement of a mechanism which can only be slowly reversible or a mechanism which is irreversible so that normalization takes place only when new red cells are released into the circulation.