This work compares the metabolism of total ketone bodies in 13 insulin-deprived, type I diabetic subjects and 26 control subjects fasted for 15 h to 23 days, with the two groups showing a similar range of ketone body levels (1-12 mM). Ketone turnover rate was measured using a primed, constant infusion of either 14C-acetoacetate or 14C-beta-hydroxybutyrate, both tracers yielding comparable results. The major conclusions of this study are the following: the kinetics of ketone bodies are comparable in the two groups within the range of concentrations tested. The hyperketonemia of fasting and diabetes is primarily caused by an increased production of ketone bodies, but the phenomenon is amplified by a progressive limitation in the ability of tissues to remove ketones from blood as the concentration rises. The inverse relationship between the metabolic clearance and the plasma levels of ketones, which underlies this process, represents a general characteristic of ketone body metabolism that applies to both types of ketosis. A maximal metabolic disposal rate of about 2.3 mmol/min/1.73 m2 is attained in both groups at concentrations of 10-12 mM, which correspond to the highest ketone body levels encountered during prolonged fasting. Thus, up to these levels, there is no evidence for the existence of a ketone body removal defect specific to diabetes.