The effect of luminal sodium on intestinal glucose absorption at a variety of glucose concentrations was studied with a segmental perfusion technique in normal subjects. Uphill glucose transport was inhibited with sodium-free perfusions with either mannitol or Tris-HCl as the osmotic replacement of sodium (P < 0.01-P < 0.001). This effect did not appear to be the result of solvent drag, as increasing net water absorption without supplying sodium to the lumen did not increase glucose absorption. Downhill glucose transport (infusion concentrations of 6.0-27.8 mmoles/liter), on the other hand, was not affected by the absence of sodium in the infusion solution. Glucose concentrations of upper intestinal fluid after normal carbohydrate meals were usually found to exceed serum concentrations; thus, downhill glucose absorption, with, at most, a very limited dependence upon intraluminal sodium concentration, may account for a significant part of normal carbohydrate absorption.