The effect of radiation therapy on substrate metabolism was evaluated in five patients with head and neck or lung cancer. Stable isotope tracer methodology was used to determine urea, amino acid, glucose, and lipid kinetics during postabsorptive conditions before initation, near the midpoint (after receiving 2,672 ± 36 rads), and at completion (after receiving 6,072 ± 307 rad) of a 6- to 8-week course of radiation therapy. Nutritional status was maintained throughout the treatment period by providing supplemental enteral feedings as needed. Postabsorptive plasma insulin, catecholamine, and amino acid concentrations did not change during the course of treatment. Before radiation therapy was initiated, values for the plasma rate of appearance (Ra) of urea (3.35 ± 0.33 μmol · kg-1 · min-1), α- ketoisocaproate ([α-KIC] 2.16 ± 0.19 μmol · kg-1 · min-1), phenylalanine (0.59 ± 0.052 μmol · kg-1 · min-1), and glucose (10.56 ± 1.31 μmol · kg-1 · min-1) were in the normal range. However, glycerol and palmitate Ra values (3.11 ± 0.30 and 2.01 ± 0.33 μmol · kg- 1 · min-1, respectively) were 25% higher than values observed previously in normal subjects. Substrate flux did not change during radiation therapy, and measurements obtained during the midpoint and at completion of treatment were similar to initial values. These results demonstrate that large doses of radiation therapy, administered over 6 to 8 weeks to the upper body, do not cause significant metabolic stress.