To examine whether lithium reabsorption varies in proportion to the bicarbonate-dependent reabsorption of water and chloride, reabsorption was altered by varying PCO2 and glomerular filtration rate (GFR) in volume-expanded, anesthetized dogs during ethacrynic acid infusion. At constant GFR and plasma bicarbonate concentration, lithium, bicarbonate, chloride and water reabsorption were inversely related to plasma pH during variations in PCO2. Lithium and bicarbonate reabsorption varied by 9 +/- 1% and chloride reabsorption by 7 +/- 1% as plasma pH was altered by 0.1 unit from plasma pH 7.5. Calculation of reabsorbate concentrations indicated that lithium was reabsorbed as readily as water (reflection coefficient = 0). During mechanical constriction of the suprarenal aorta, GFR was reduced at constant plasma pH. Bicarbonate reabsorption fell more than chloride, water and lithium reabsorption. Lithium reabsorption was not significantly reduced until GFR was reduced by 35%. In stop-flow studies during ouabain infusion, urinary lithium concentrations were reduced below plasma concentrations. This is compatible with passive diffusion of lithium along a lumen-positive potential exceeding 10 mV in the diluting segment. Thus, lithium reabsorption behaved as expected for bicarbonate-dependent paracellular reabsorption during variations in PCO2; when GFR is reduced, an additional component of lithium reabsorption is disclosed.