This study examined oxidative metabolism and thermogenesis in the acute response to controlled intravenous nutrition in seven cancer patients who lost weight. Six weight-losing and malnourished patients without cancer served as controls. Indirect calorimetry was used and measurements of arterial concentrations of various substrates, metabolic end products, and insulin were performed. Resting energy expenditure (REE) was measured after an overnight fast. The resting energy need was calculated for each patient according to REE. The nutrition program consisted of glucose and lipids (Intralipid KabiVitrum AB, Stockholm, Sweden) each as 50% of nonprotein calories and amino acids (6.9 mg N/kcal). These substrates were infused simultaneously at rates equivalent to one, two, and three times REE, over periods of 6.5 hours on 3 consecutive days after a 12-hour fast. Arterial substrate levels and energy expenditure were measured between 6 and 6.5 hours after the start of the infusion. The cancer patients had well-recognized metabolic changes in the fasted state, such as elevated plasma levels of glycerol, triglycerides, free fatty acids, and lactate, and higher energy expenditure than predicted. The cancer patients responded to strictly defined substrate challenge in a similar way as the malnourished patients without cancer. Whole body oxidative capacity and the proportion of infused glucose and lipids that were oxidized at different levels of infusion rates were not decreased in cancer patients compared with control patients. Similar arterial substrate concentrations among the groups during infusions argues for a maintained plasma clearance of the substrate in the cancer patients. This study supports the suggestion that cachectic cancer patients can generate and conserve energy normally in response to intravenous nutrition. This refers to cancer patients with a history of weight loss up to 15% of their normal body weight. Therefore, weight loss due to altered tumor-host metabolism in cancer patients is of quantitative importance in the fasted state rather than in the fed state.