The gut is classically seen as the main source of circulating ammonia. However, the contribution of the intestines to systemic ammonia production may be limited by hepatic extraction of portal-derived ammonia. Recent data suggest that the kidney may be more important than the gut for systemic ammonia production. The aim of this study was to quantify the role of the kidney, intestines and liver in interorgan ammonia trafficking in humans with normal liver function. In addition, we studied changes in interorgan nitrogen metabolism caused by major hepatectomy. From twenty-one patients undergoing surgery, blood was sampled from the portal, hepatic and renal veins to assess intestinal, hepatic and renal ammonia metabolism. In 7 cases blood sampling was repeated after major hepatectomy. At steady state during surgery, intestinal ammonia release was equalled by hepatic ammonia uptake, precluding significant systemic release of intestinal-derived ammonia. In contrast, the kidneys released ammonia to the systemic circulation. Major hepatectomy led to increased concentrations of ammonia and amino acids in the systemic circulation. However transsplanchnic concentration gradients after major hepatectomy were similar to baseline values, indicating the rapid institution of a new metabolic equilibrium. In conclusion, since hepatic ammonia uptake exactly equals intestinal ammonia release, the splanchnic area, and hence the gut, does probably not contribute significantly to systemic ammonia release. After major hepatectomy, hepatic ammonia clearance is well-preserved, probably related to higher circulating ammonia concentrations.