1. We have previously shown that the ratio (RWBP) of incorporation of label from 2-ketoisocaproate (KIC) into the leucine of whole-body protein to the simultaneous incorporation of label from leucine itself into protein is a measure of the nutritional efficiency of KIC as a substitute for leucine. 2. In order to determine whether RWBP can be estimated indirectly from measurement of labelled CO2 excretion, rats were injected orally or intravenously with [4,5-3H]leucine and either [1-14C]leucine or [1-14C]KIC. Expired CO2 was collected for 6 h. 3. The results show that 9-14% of KIC underwent first-pass oxidation after oral administration. When isotopes were given intravenously, the mean rate of excretion of 14CO2 from KIC, after 20 min, remained 1.8 times the mean rate of excretion of 14CO2 from leucine. 4. Mean RWBP, measured in whole-body protein in rats given isotopes orally or intravenously along with small or large doses of carriers, was the same as mean RWBP estimated from mean cumulative CO2 excretion. 5. We conclude (1) that nutritional efficiency of KIC relative to leucine can be estimated from measurement of labelled CO2 excretion, and (2) that the relative inefficiency of KIC as a substitute for leucine in the rat is attributable to first-pass oxidation of 9-14% (when given orally) and 80% greater susceptibility to systemic oxidation than leucine.