Abstract 1. 1. Glucose formation from various precursors by the perfused guinea-pig liver was inhibited by certain indole derivatives including tryptophan metabolites (see Fig. 1) at 0.1 mM. 2. 2. Neither mitochondrial nor cytosolic phosphoenolpyruvate carboxykinase activity was affected by the inhibitors. However, the ability of isolated, intact mitochondria to form phosphoenolpyruvate was strongly inhibited by indole compounds with 2-oxoglutarate but less affected with malate as substrate. 3. 3. Inhibitors induced a decrease of ATP and an increase of ADP and AMP content of the livers perfused with pyruvate or with pyruvate + octanoate. 4. 4. The tested indole compounds inhibited mitochondrial respiration with NAD-dependent substrates but did not affect it with succinate. 5. 5. Finally, a decrease of dinitrophenol-ATPase to Mg 2+ -ATPase ratio was induced by the tested indole compounds. 6. 6. The suggestion is made that inhibition by indolic compounds of gluconeogenesis in guinea-pig liver is due to alterations induced by the compounds in oxidative phosphorylation rather than to a direct inhibition of phosphoenolpyruvate carboxykinases.