S-adenosylhomocysteine (SAH), the metabolic precursor of homocysteine in the body, is a potent inhibitor of methylation reactions. Several methylation reactions play a major role in epigenetic regulation of protein expression, atherosclerosis, and cancer development. Here we studied the mechanisms responsible for the maintenance of circulating SAH levels by measurement of the arterio-venous differences across the kidney, splanchnic organs, and the lung in humans. The lungs did not remove or add any circulating SAH, whereas the liver released it into the hepatic veins. The kidney extracted 40% of SAH and the SAH arterio-venous difference across the kidney was directly and significantly related to its arterial levels. Thus, the kidney plays a major role in maintaining SAH levels and may, indirectly, control tissue transmethylation reactions. Our findings of a pivotal role for the human kidney in sulfur amino acid metabolism may also account for the increased plasma levels of SAH in patients with chronic kidney diseases.