Upper gastrointestinal (UGI) bleeding in cirrhosis is associated with enhanced ammoniagenesis, the site of which is thought to be the colon. The aims of this study were to evaluate interorgan metabolism of ammonia following an UGI bleed in patients with cirrhosis. Study 1: UGI bleed was simulated in 8 patients with cirrhosis and a transjugular intrahepatic portasystemic stent-shunt (TIPSS) by intragastric infusion of an amino acid solution that mimics the hemoglobin molecule. We sampled blood from the femoral artery and a femoral, renal, portal, and hepatic vein for 4 hours during the simulated bleed and measured plasma flows across these organs. Study 2: In 9 cirrhotic patients with an acute UGI bleed that underwent TIPSS insertion, blood was sampled from an artery and a hepatic, renal, and portal vein, and plasma flows were measured. Study 1: During the simulated bleed, arterial concentrations of ammonia increased significantly (P =.002). There was no change in ammonia production from the portal drained viscera, but renal ammonia production increased 6-fold (P =.008). In contrast to an unchanged ammonia removal by the liver, a significant increase in muscle ammonia removal was observed. Study 2: In patients with an acute UGI bleed, ammonia was only produced by the kidneys (572  nmol/kg bw/min) and not by the splanchnic area (-121  nmol/kg bw/min). In conclusion, enhanced renal ammonia release has an important role in the hyperammonemia that follows an UGI bleed in patients with cirrhosis. During this hyperammonemic state, muscle is the major site of ammonia removal.