Summary In the regulation of ketone body formation the citrate synthase reaction occupies a key position in determining the metabolic fate of liver acetyl-CoA. As a factor which might shift acetyl-CoA from the oxidative pathway into direction of acetoacetate condensation by blocking the citric acid cycle a decrease of liver oxalacetate has been found in diabetic and fat-fed ketotic rats. Furthermore, an inhibition of citrate synthase in vitro in the presence of physiological concentrations of palmityl-CoA was observed. The inhibition is competitive with respect to oxalacetate but not with respect to acetyl-CoA (“allosteric inhibition”) and can be partially reversed by serum albumin. The mode of action of palmityl-CoA which lowers the affinity of the enzyme for oxalacetate in association with the reduction in liver oxalacetate levels can be considered as a sensitive regulatory system for the control of ketone body formation in liver.