Renal de novo arginine production has been suggested to be crucial for regulation of arginine production in disease. We investigated how the interorgan pathway for de novo arginine production is affected by the presence of malignant tumor and/or surgical trauma. Controls and methylcholanthrene-sarcoma-bearing mice were studied, both with and without undergoing laparotomy (n = 9-13 per group). One day after laparotomy, amino acid fluxes across the hindquarter, intestine, liver, and kidney were studied. In contrast to healthy mice, the liver of tumor-bearing mice took up citrulline (9 +/- 3 vs 1 +/- 2 nmol/[10 g min], P < .05), simultaneous with attenuated renal arginine output (4 +/- 3 vs 12 +/- 2 nmol/[10 g min], P < .05), despite increased intestinal conversion of glutamine to citrulline (15 +/- 3 vs 8 +/- 1 nmol/[10 g min], P < .05). In tumor-bearing mice undergoing surgery, intestinal citrulline output decreased (from 15 +/- 3 to 8 +/- 2 nmol/[10 g min], P < .05) and renal arginine output remained close to zero despite increased renal citrulline uptake (from 6 +/- 2 to 12 +/- 2 nmol/[10 g min], P < .05). In conclusion, the interorgan pathway for de novo arginine production was differently regulated depending on the pathophysiological situation. In methylcholanthrene-sarcoma-bearing mice, decreased de novo arginine production was accompanied by the presence of hepatic citrulline uptake, whereas tumor-bearing mice subjected to surgical trauma showed concomitant decreased intestinal citrulline output.