Summary. Movement of C1 from the lumen of Necturus proximal tubule into the cells is mediated and dependent on the presence of luminal Na. Intracellular C1 activity was monitored with ion selective microelectrodes. In C1 Ringer's perfused kidneys, cell C1 activity was 24.5_+ 1.1 mM, 2 to 3 times higher than that predicted for passive distribution. When luminal NaC1 was partially replaced by mannitol (capillaries perfused with C1 Ringer's) cell C1 decreased showing a sigmoidal dependence on luminal NaC1. Peritubular membrane potential was unaltered. Sulfate Ringer's perfusion of the kidneys washed out all cell C1 but did not alter peritubular membrane potential. Chloride did not enter the cell when the tubule lumen was perfused with 100 mM KC1, LiC1, or tetramethylammonium C1. Luminal perfusion of NaC1 caused cell CI to rise rapidly to the same value as the controls in the C1 Ringer's experiments. Perfusion of the tubule lumen with mixtures of NaC1 and NazSO~, while the capillaries contained sulfate Ringer's yielded a sigmoidal dependence of cell C1 on luminal NaC1 activity. Chloride movement from the lumen into the proximal tubule cells required approximately equal concentrations of Na and C1. Current clamp experiments indicated that intracellular chloride activity was insensitive to alterations in luminal membrane potential, suggesting that chloride entry was electrically neutral. The transcellular chloride flux was calculated to constitute about one half of the normal chloride reabsorption rate. We conclude that the cell C1 activity is primarily determined by the NaC1 concentration in the tubule lumen and that C1 entry across the luminal membrane is mediated.Reabsorption of chloride by the Necturus proximal tubule has been explained on the basis of passive driving forces. The transepithelial potential difference (PD), oriented lumen negative, of 10 to 15 mV is thought to provide sufficient driving force to move chloride across the permeable extracellular shunt pathway [5,6, 17,18]. However, the ratio of the chloride concentration in the tubule lumen to that of the plasma is always near 1.0, which does not agree with the value predicted from the transepithelial PD for a passively distributed ion [2,6,8]. In addition, intracellular chloride activity in Necturus proximal tubule cells is about