Lithium clearances were performed in conscious dogs on varying sodium intakes. Fractional lithium excretion (FE-Li) was 22.6 +/- 2.2% in sodium-replete dogs (fractional sodium excretion, FE-Na greater than 0.4%, n = 11) but only 6.9 +/- 2.3% in sodium-depleted dogs (FE-Na less than 0.4%, n = 25). In 4 markedly sodium-depleted dogs (FE-Na 0.03 +/- 0.02%) the distally acting diuretic amiloride caused an 8-fold increase in FE-Li (from 1.5 +/- 1.0 to 11.6 +/- 2.0%). Our data suggest that tubular reabsorption of lithium in sodium-depleted dogs is not restricted to the proximal tubules but also occurs in the distal nephron. Therefore the lithium clearance cannot be used as an index of sodium and filtrate delivery from the proximal tubules in sodium-depleted dogs.