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In an attempt to define the mechanism of weight loss in cancer patients, fat and carbohydrate oxidation rates were calculated in 93 patients. Seventy patients with colorectal or gastric cancer were compared with a control group of 23 patients with non-malignant illness. Twenty-seven patients with cancer and 13 control patients had lost more than 10% of their preillness body weight. Fat and carbohydrate oxidation rates were derived from measurements of oxygen consumption, carbon dioxide production, and urinary nitrogen excretion. Patients with cancer had significantly higher fat oxidation rates (p < 0.01) and significantly lower carbohydrate oxidation rates (p < 0.05) when compared with controls. Weight-losing cancer patients had significantly higher fat oxidation rates when compared with weight-stable cancer patients (p < 0.02), weight-stable controls (p < 0.01), and weight-losing controls (p < 0.02). Cancer patients with liver metastases (N = 14) had significantly higher fat oxidation rates (p < 0.01) and significantly lower carbohydrate oxidation rates (p < 0.01) compared with cancer patients who had localized disease. There were no significant differences among the groups with respect to resting energy expenditure when expressed as kilocalorie per kilogram lean body mass per day. The presence of cancer appears to be associated with abnormal fat and carbohydrate metabolism. The increased rate of fat oxidation seen in patients with cancer, especially those with weight loss or liver metastases, may be a significant factor in the development of cancer cachexia.