Lithium and sodium are normally reabsorbed in parallel with water by the renal proximal tubule whereby their tubular fluid-to-plasma concentration ratios (TF/P) remain close to unity throughout the proximal convoluted segment. During osmotic diuresis, the late proximal (TF/P)Na is known to decrease. The present experiments were undertaken to study whether the late proximal TF/P for Li decreases like that of Na during osmotic diuresis. Data were obtained in a control period (C) and in two successive periods during mannitol diuresis (P1, P2). Glomerular filtration rate decreased gradually during osmotic diuresis [1,147 +/- 32 (C) to 950 +/- 22 (P2) microliters.min-1.g kidney wt (KW)-1, P less than 0.01), whereas Li clearance (CLi) increased [377 +/- 21 (C) to 469 +/- 28 (P1, P less than 0.01) and 408 +/- 25 (P2, NS) microliters.min-1.gKW-1, respectively]. (TF/P)Na decreased from 0.98 +/- 0.02 (C) to 0.89 +/- 0.02 (P less than 0.01) and 0.90 +/- 0.04 (P less than 0.05) (P1 and P2, respectively). (TF/P)Li was close to, but significantly higher than, unity during control (1.09 +/- 0.02), but, in contrast to (TF/P)Na, it did not decrease significantly during osmotic diuresis. Delivery of water from the proximal straight segment, as estimated from CLi/CIn, increased in proportion to the delivery from the convoluted segment, as estimated from 1/(TF/P)In. It is concluded that the proximal net Li reabsorption follows more closely the net water reabsorption than the net Na reabsorption during osmotic diuresis.