Acid-base balance during development of diabetic ketoacidosis was reappraised on the basis of old studies on urinary excretion of ions. Circulatory collapse with impaired urinary excretion of acids is a prominent feature of the late phase of diabetic ketoacidosis, in which pathophysiological measurements are difficult to make. To elucidate the balance between hepatic uptake of carboxylic acids (free fatty acids and lactate plus pyruvate) and hepatic release of carboxylic acids (ketone bodies and lactate plus pyruvate) during the late phase of diabetic ketoacidosis, perfused livers from normal and streptozotocine-diabetic rats, fasted for 48 h, were subjected to high perfusate glucose concentrations, low perfusate pH and low perfusate flow rates. Provided that flow was kept normal, there was always a net uptake of carboxylic acids. At normal flow, a low pH and a high glucose concentration in the perfusate did not affect the hepatic uptake of lactate plus pyruvate or the flux of carbon from lactate to glucose. Reduction of the perfusate flow rate by two-thirds invariably turned the liver into a state of net carboxylic acid production. The net uptake of lactate plus pyruvate was greatly reduced, mainly due to initiation of a glycolytic flux.