Pathophysiological concentrations of branched chain keto-acids (BCKAs), such as those that occur in maple syrup urine disease, inhibit oxygen consumption in liver homogenates and brain slices and the enzymatic activity of α-ketoglutarate- and pyruvate dehydrogenase complexes. Consistent with previous work, studies in isolated rat liver mitochondria indicate that three BCKAs, α-ketoisocaproate (KIC), α-keto-β-methylvalerate (KMV) and α-ketoisovalerate (KIV), preferentially inhibited State 3 respiration supported by α-ketoglutarate relative to succinate or glutamate/malate (KIC, >100-fold; KMV, >10-fold; KIV, >4-fold). KIC was also the most potent inhibitor (Ki,app 13 ± 2 μM). Surprisingly, sub-inhibitory concentrations of KIC and KMV can markedly stimulate State 3 respiration of mitochondria utilizing α-ketoglutarate and glutamate/malate, but not succinate. The data suggest that physiological concentrations of the BCKAs may modulate mitochondrial respiration.