We sought to determine the role the liver might play in the regulation of anion-cation balance during both stable baseline conditions and acute endotoxemia. Ten pentobarbital sodium-anesthetized dogs were instrumented at laparotomy with ultrasonic flow probes around the left renal artery, portal vein, and hepatic artery, and catheters were inserted into the hepatic vein, portal vein, pulmonary artery, left renal vein, and abdominal aorta. Measurements were obtained from each site at baseline and 30-45 min after the intravenous infusion of endotoxin. The total anion flux across the liver was calculated from the strong-ion difference. At baseline, the liver removed anions from the circulation (-0.34 meq/min). With early endotoxemia, however, the liver switched to the release of anions (0.12 meq/min; P = 0.0046). After endotoxin administration, the gut, which was neutral at baseline, began to take up anions (-0.47 meq/min; P = 0.008). Anion flux across the lung and kidney was unchanged. We conclude that in the dog the liver, which removes anions at baseline, switches to release anions during early endotoxemia and may be a major site of acid production in early sepsis.