Active glucose absorption increases passive, paracellular absorption of small solutes. Absorption of larger molecules by this mechanism has not been verified in humans under physiological conditions. The purpose of this study was to determine if ingestion of a glucose solution enhances absorption of mannitol in humans. Mannitol (182 Da) is a non-metabolizable molecule believed to be absorbed only via the paracellular route. Its urinary excretion therefore may serve as an index for paracellular absorption of similar-sized solutes, such as glucose (180 Da) and amino acids (average 138 Da). Eight healthy individuals (five females, three males; mean age = 22 +/- 1 yrs) ingested a 4% glucose/0.2% mannitol solution or a 4% fructose/0.2% mannitol solution using a randomized, balanced design. Urine was collected for 5 h and mannitol excretion determined. Ingestion of the glucose solution increased (p < 0.05) mannitol excretion (0.52 +/-0.27 g) compared to the fructose solution (0.39 +/-0.13 g), a 33% increase. These results indicate glucose promotes passive absorption of nutrient-sized solutes, likely via the paracellular route. This may explain how humans can absorb high amounts of glucose when maximal active transport is exceeded. Furthermore, other nutrients such as amino acids may utilize this route, thereby enhancing absorption.