The hypothesis that a high-fat parenteral regimen was beneficial for respiratory gas exchanges, in comparison with a high-glucose regimen, was tested in a paired crossover design. Ten parenterally fed newborn infants with no respiratory problems received two 5-day isoenergetic and isonitrogenous regimens that differed in their nonprotein source of energy; the level of fat intake (low fat (LF) 1 gm.kg-1.day-1; high fat (HF) 3 gm.kg-1.day-1) varied inversely with that of glucose. Continuous transcutaneous PO2 (tcPO2) and PCO2 (tcPCO2), respiratory gas exchange (indirect calorimetry), and plasma arachidonate metabolites were measured at the end of each regimen. Oxygen consumption and resting energy expenditure were not affected by modification of the source of energy. However, carbon dioxide production (VCO2) was higher during LF than during HF (6.9 +/- 0.2 vs 6.2 +/- 0.1 ml.kg-1.min-1; p less than 0.01), as was the respiratory quotient (1.08 +/- 0.02 vs 0.96 +/- 0.02; p less than 0.001). Despite the differences in VCO2, the tcPCO2 was not affected, suggesting adequate pulmonary compensation during LF, as documented by the higher minute ventilation (160 +/- 7 vs 142 +/- 5 ml.kg-1.min-1; p less than 0.01). The lower tcPO2 during the HF regimen (73.8 +/- 2.8 vs 68.8 +/- 2.6 mm Hg; p less than 0.015) indicated a disturbance at the alveolocapillary level induced by the lipid emulsion. No differences were found in circulating levels of prostaglandins and thromboxanes. The substitution of glucose for lipid did not modify fat storage (2.1 +/- 0.3 vs 2.1 +/- 0.3 gm.kg-1.day-1). We conclude that the supposed beneficial effect of a fat emulsion on respiratory gas exchange is questionable.