The purpose of this study was to investigate whether a high fat intake would potentiate an excess of fructose in the diet of rats to alter energy metabolism and worsen the nutritional status for copper. Weanling male rats were fed diets with 45% fat and 20% cornstarch, 45% fat and 20% fructose, 5% fat and 60% cornstarch, or 5% fat and 60% fructose for 3 wk, with either sufficient (+) or deficient (-) amounts of copper. Copper deficiency, as demonstrated by low plasma copper and ceruloplasmin, caused a decrease of liver, heart, and testes copper; a decline of liver and heart zinc; and an increase of hepatic iron. High-fat diets reduced liver glucose-6-phosphate dehydrogenase (G6PDH) and, to a lesser extent, glycerophosphate dehydrogenase (GPDH). The interaction between high-fat and high-fructose diets, superimposed on copper deficiency, resulted in a lowering of G6PDH, GPDH, and malic enzyme. These results support the hypothesis that a high fat ingestion becomes an aggravating stress factor, which, in combination with a high-fructose intake in a copper-deficient diet, adversely alters key organ mineral content, with detrimental effects on copper nutritional status and intermediary metabolism.