Adult male rats were fed on a control diet containing (g/kg) carbohydrate 600, lipid 35 and protein 190, or on a high-fat diet containing carbohydrate 360, lipid 420 and protein 120. After 30 d, the high-fat diet provoked a decrease in serum cholinesterase (EC 3.1.1.8) activity which was reversed by feeding rats on the control diet. The observed decrease after 90 d on the high-fat diet was not seen if a simultaneous daily intraperitoneal injection of a lipotrophic agent containing (mg/kg) S-adenosyl-L-methionine 3, coenzyme A 0.1, UDP-glucose 30 and CDP-choline 1.5 was given to rats on the high-fat diet. The findings are discussed in relation to the apparent susceptibility of serum cholinesterase to dietary components and its possible role in lipid metabolism.