Definition of mechanisms of cachexia and inanition in cancer should improve treatment. To determine the interrelationships between tumor substrate metabolism, caloric intake, and body weight, 24 Buffalo rats were studied. Twelve rats had Morris 7777 tumors implanted and twelve were controls. Animals had daily weights and rat chow intake measured. When tumor-bearing animals lost significant weight (P < 0.05, t test), they were sacrificed with a control animal. The liver from experimental and control animals and the hepatoma from the thigh were excised, homogenized, and mitochondria were isolated. The adenosine diphosphate (ADP)-stimulated respiratory activity (state 3) and ADP-independent respiratory activity (state 4) of mitochondria were determined. The Respiratory Control Index (RCI) was calculated as the most sensitive indicator of mitochondrial oxygen-substrate metabolism. Tumor-burdened rats and controls had statistically equivalent chow consumption (P > 0.05). Tumor mitochondria demonstrated reduced rates of state 3 and state 4 oxygen consumption and RCIs were statistically less than control liver tissue (P < 0.05). From these data we conclude: (1) weight loss in this tumor model is not due to inadequate intake; (2) hepatoma mitochondria are inefficient in use of substrates; and (3) exhaustion of substrates in an inefficient manner may contribute to the catabolism of cancer. © 1980.