The effect of radiation therapy on substrate metabolism was evaluated in five patients with either 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 2672+36 rads), and at the completion (after receiving 6072+307 rads) of a 68 wk 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, the plasma rate of appearance (Ra) of urea (3.35+0.33 umol.kg-1.min-1), a-ketoisocaproate (2.16+0.19 umol.kg-1 .min-1), phenylalanine (0.59+0.052 umol.kg-1.min-1), and glucose (10.56+1.31 umol.kg-1.min-1) were in the normal range. Glycerol and palmitate Ra (3.11+0.30 and 2.01+0.33 umol.kg-1.min-1, respectively), however, 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 the completion of treatment were similar to initial values. These results demonstrate that large doses of radiation therapy, given over 68 wk to the upper body, does not cause significant metabolic stress.