The effect of tumor burden in acute lymphoblastic leukemia on resting energy expenditure, thermic effect of food, and substrate utilization was investigated with open-circuit indirect calorimetry after an overnight fast. Nine patients (six females, three males) ages 6.5 to 15.8 y were studied. Patients were divided into two groups according to their tumor burden at diagnosis (i.e. white cell count, presence or absence of mediastinal mass, or massive organomegaly). The patients with a greater tumor burden had increased energy expenditure. Their resting energy expenditure returned to normal in response to chemotherapy. These results must be interpreted with caution due to the small patients numbers (high tumor burden n = 3; low tumor burden n = 6). Substrate utilization was altered by chemotherapy with an increase in carbohydrate utilization and a decrease in fat oxidation (p less than 0.009). The magnitude of the thermic effect of food tended to increase on treatment (p less than 0.016). Inasmuch as most chemotherapy programs for children last up to 3 y, we believe it is important that the effects of chemotherapy on intermediary metabolism be studied, particularly in relationship to any possible permanent effects on growth and development.