As the population of nephrons is reduced, sodium excretion per nephron must increase if sodium balance is to be maintained. The mechanism of this adjustment was studied in rats in which 50% and approximately 85% of renal tissue was excised. Although glomerular filtration per remaining nephron rose after uninephrectomy, it did not rise further when more renal tissue was removed, even though sodium excretion per nephron mounted. Hyperfiltration does not, therefore, account for the stepwise increase in sodium excretion per nephron with progressive renal ablation. Proximal tubular absorption, estimated by reabsorption half-time, was unchanged by renal insufficiency, indicating that “third factor” did not produce the observed changes in sodium excretion per nephron. It seems likely that the earliest adjustments in sodium excretion in renal failure take place in the distal tubules of healthy nephrons, and that they are conditioned by changes in the osmotic load per nephron.