The validity of the lithium clearance technique as a measure of end-proximal fluid delivery was assessed using micropuncture in sodium-replete, Inactin-anesthetized Sprague-Dawley rats. Three groups of animals were used: controls, amiloride treated, and furosemide treated. Diuretic-induced salt and water losses were replaced. Fractional lithium excretion (FELi) was 0.23 +/- 0.01, 0.24 +/- 0.02, and 0.40 +/- 0.03 in the control, amiloride, and furosemide groups, respectively. In each group, the tubular fluid-to-plasma lithium concentration ratio at the end of the proximal convoluted tubule (PCT) was significantly greater than unity (control, 1.16 +/- 0.03; amiloride, 1.16 +/- 0.02; furosemide, 1.17 +/- 0.02). In the control group, fractional lithium delivery (FDLi) at the late PCT was 0.50 +/- 0.02, while FDLi at the early distal tubule was 0.25 +/- 0.01; the latter did not differ significantly from FDLi at the late distal tubule or from FELi. Values in amiloride-treated rats were almost identical. Furosemide had no effect on FDLi at the late PCT, but raised that at the early distal tubule to 0.37 +/- 0.03. We conclude that 1) lithium reabsorption in the PCT lags slightly behind that of water, 2) substantial furosemide-sensitive lithium reabsorption occurs beyond the PCT, and 3) no significant lithium reabsorption occurs in nephron segments beyond the loop. These findings call into question the use of lithium clearance as a quantitative measure of end-proximal fluid delivery in sodium-replete animals.