Switching in acidosis of hepatic nitrogen disposal from urea synthesis to NH4+ and net glutamine production was demonstrated in the isolated perfused livers of starved male Wistar rats. Lactate was preferred to glucose as the substrate for the carbon skeleton of glutamine synthesized over the pH range 6.9-7.5. This is necessary if the switch away from a proton-producing process (ureagenesis) in acidosis is to constitute an acid-base regulating system intrinsic to the liver. Glutamine balance shifted with pH from marked net uptake to small net output under acidotic conditions (pH 7.5-6.9), an effect due solely to a decrease in glutamine uptake. NH4+ uptake by the liver had a linear relationship with pH, being markedly decreased in acidosis because glutamine synthesis was insufficient to compensate for the decreased incorporation into urea. Animals rendered chronically acidotic showed a lower central venous plasma urea concentration and a raised NH4+ concentration, but their livers synthesized no more glutamine when perfused at an acidotic pH than did normal livers. We conclude that perivenous hepatocytes may not be efficient scavengers of NH4+ ions, which must be partly disposed of elsewhere by non-proton-generating pathways if inhibition of ureagenesis is to represent a hepatic acid-base regulating system.