Leptin is a pleiotropic hormone known for its effects in regulating appetite. Recently data have shown that leptin in circulation enters the lumen of the digestive tract in a form with signaling potential (1). To explore this further an experiment was designed to examine the fate of leptin in the digestive tract. Leptin was labeled with 125I using the Iodogen method. Random bred male Swiss mice aged 8 weeks were lightly anaesthetized using ether to prevent damage to the esophagus before receiving 12 ng 125I-leptin by intragastric gavage. Animals were returned to individual cages until being euthanized over a time course of up to 120 min (n = 4 per time) before tissues were collected to determine 125I-leptin distribution. Samples were collected and subjected to trichloroacetic acid (TCA) precipitation to confirm intactness of the tracer. All procedures were performed in accordance with the NHMRC Code for the Care and Use of Animals for Scientific Purposes. Data are presented as mean ± SE. 125I-leptin was detected in all samples examined. Recovery from the lumen of the stomach declined to 23.5 ± 2.2 % of the dose 120 min after administration. In the lumen of the small intestine a wave of approximately 3 – 8 % of the dose was recorded in increasingly distal portions of the small intestine over the duration of the experiment. In the hindgut 0.7 ± 0.4 % of the administered dose was recovered from the lumen 30 min after administration, increasing to 3.9 ± 1.7 % 120 min after administration. At all times sampled 125I-leptin was recovered from the blood, with calculated recovery for the entire circulation ranging between 3.0 ± 1.2 % 90 min after administration and 4.1 ± 0.5 % 45 min after administration. 125I-leptin in the circulation was found to be 73 ± 6.2 % (n = 3) intact after TCA precipitation, indicating signaling potential. The experiment described is the first to examine leptin pharmacokinetics in the digestive tract. The data indicate that leptin in the digestive tract is capable of entering the circulation in a form with potential signaling capacity. Leptin introduced into the stomach progressed distally over the course of the experiment with less than 4 % of the administered dose detected in the hindgut, while at all times sampled approximately 3.7 % of the administered dose was calculated to be in the circulation. These data suggest that leptin in the digestive tract is potentially being absorbed from the small intestine. When considered with a recent report (1), it appears that leptin may cycle between the circulation and the digestive tract. The potential reason for this is unclear, however knockout of Lep-Rb (the principal leptin receptor) from mouse small intestine has conferred a resistance to diet induced obesity (2), suggesting leptin may play a role in regulating nutrient absorption from the digestive tract.