Inborn errors of 3 of the 4 enzymes specific for gluconeogenesis are known. The present report describes a deficiency of the 4th enzyme phosphoenolpyruvate carboxykinase (PEP-CK). characterized by severe hypoglycemia and extreme fatty changes of liver and kidney. A liver biopsy, taken immediately after death, demonstrated increased activities of glucose-6-phosphatase, fructose-1,6-diphosphatase and pyruvate carboxylase (40.6, 15.9 and 3.3 μmoles per min. per g w.w. respectively) and a decreased activity of PEP-CK (0.7 μmoles per min. per g w.w.). The low activity of PEP-CK can explain the hypoglycemia. Light and electron microscopy showed extreme fatty changes of the liver and of the proximal tubuli of the kidney. The liver contained 55% (of wet weight) of chloroform-methanol extractable material. The fatty acid composition of these lipids showed an increased content of the C12 and C14 acids, pointing to an increased rate of fatty acid synthesis. These fatty changes may be explained by the specific localization of PEP-CK in man: for 80% in the mitochondria. In the absence of PEP-CK overproduction of citrate may occur, which will leave the mitochondria in exchange for malate, giving rise to the operation of a “citrate-malate” cycle. The net result of such a cycle will be the transfer of acetyl-CoA to the cytoplasm where it may serve as substrate for fatty acid synthetase.